Compounds and compositions for treating conditions associated with NLRP activity

ABSTRACT

In one aspect, compounds of Formulae (I) and (II), or pharmaceutically acceptable salts thereof, are featured: Formulae (I) and (II), wherein the variables shown in Formulae (I) and (II) can be as defined anywhere herein.

This application is a National Stage application under 35 U.S.C. § 371 of International Patent Application No. PCT/US2017/028166, filed Apr. 18, 2017, which claims priority to U.S. Provisional Patent Application Ser. Nos. 62/324,081, filed Apr. 18, 2016 and 62/324,071, filed Apr. 18, 2016.

TECHNICAL FIELD

This disclosure features chemical entities (e.g., a compound that modulates (e.g., antagonizes) NLRP1 or NLRP3 or both NLRP1 and NLRP3, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that are useful, e.g., for treating a condition, disease or disorder in which a decrease or increase in NLRP1/3 activity (e.g., an increase, e.g., a condition, disease or disorder associated with NLRP1/3 signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder in a subject (e.g., a human). This disclosure also features compositions as well as other methods of using and making the same.

BACKGROUND

The NLRP3 inflammasome is a component of the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as the cryopyrin associated periodic syndromes (CAPS). The inherited CAPS Muckle-Wells syndrome (MWS), familial cold autoinflammatory syndrome (FCAS) and neonatal onset multi-system inflammatory disease (NOMID) are examples of indications that have been reported to be associated with gain of function mutations in NLRP3.

The NLRP1 inflammasome is a component of the inflammatory process and its aberrant activation is pathogenic in inherited disorders such as generalized vitiligo associated with autoimmune disease (autoimmune thyroid disease, latent autoimmune diabetes in adults, rheumatoid arthritis, psoriasis, pernicious anemia, systemic lupus erythematosus, and Addison's disease).

NLRP1 and NLRP3 can form a complex and they have been implicated in the pathogenesis of a number of complex diseases, including but not limited to metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout, as well as diseases of the central nervous system, such as Alzheimer's disease and multiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinson disease, lung disease, such as asthma and COPD and pulmonary idiopathic fibrosis, liver disease, such as NASH syndrome, viral hepatitis and cirrhosis, pancreatic disease, such as acute and chronic pancreatitis, kidney disease, such as acute and chronic kidney injury, intestinal disease such as Crohn's disease and Ulcerative Colitis, skin disease such as psoriasis, musculoskeletal disease such as scleroderma, vessel disorders, such as giant cell arteritis, disorders of the bones, such as osteoarthritis, osteoporosis and osteopetrosis disorders, eye disease, such as glaucoma and macular degeneration, diseases caused by viral infection such as HIV and AIDS, autoimmune diseases such as rheumatoid arthritis, systemic Lupus erythematosus, autoimmune thyroiditis; Addison's disease, and pernicious anemia, cancer and aging.

In light of the above, it would be desirable to provide compounds that modulate (e.g., antagonize) NRLP1/3, wherein the compounds inhibit NLRP1 or NLRP3 or both NLRP3 and NLRP1.

SUMMARY

This disclosure features chemical entities (e.g., a compound that modulates (e.g., antagonizes) NLRP1 or NLRP3 or both NLRP1 and NLRP3, or a pharmaceutically acceptable salt, and/or hydrate, and/or cocrystal, and/or drug combination of the compound) that are useful, e.g., for treating a condition, disease or disorder in which a decrease or increase in NLRP1 or NLRP3 or both NLRP1 and NLRP3 activity, also referred to herein “NLRP1/3” activity (e.g., an increase, e.g., a condition, disease or disorder associated with NLRP1/3 signaling).

This disclosure also features compositions as well as other methods of using and making the same.

An “antagonist” of NLRP1/3 includes compounds that inhibit the ability of NLRP1/3 to induce the production of IL-1β and/or IL-18 by directly binding to NLRP1/3, or by inactivating, destabilizing, altering distribution, of NLRP1/3 or otherwise.

In one aspect, compounds of Formula I, or a pharmaceutically acceptable salt thereof, are featured:

or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula I can be as defined anywhere herein.

In one aspect, compounds of Formula II, or a pharmaceutically acceptable salt thereof, are featured:

or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula II can be as defined anywhere herein.

In one aspect, pharmaceutical compositions are featured that include a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same) and one or more pharmaceutically acceptable excipients.

In one aspect, methods for modulating (e.g., agonizing, partially agonizing, antagonizing) NLRP1 or NLRP3 or both NLRP1 and NLRP3 activity are featured that include contacting NLRP1 or NLRP3 or both NLRP1 and NLRP3 with a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same). Methods include in vitro methods, e.g., contacting a sample that includes one or more cells comprising NLRP1 or NLRP3 or both NLRP1 and NLRP3 (also referred to herein as “NLRP1/3”), as well as in vivo methods.

In a further aspect, methods of treatment of a disease in which NLRP1/3 signaling contributes to the pathology and/or symptoms and/or progression of the disease are featured that include administering to a subject in need of such treatment an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

In a further aspect, methods of treatment are featured that include administering to a subject a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same), wherein the chemical entity is administered in an amount effective to treat a disease in which NLRP1/3 signaling contributes to the pathology and/or symptoms and/or progression of the disease, thereby treating the disease.

Embodiments can include one or more of the following features.

The chemical entity can be administered in combination with one or more additional therapies with one or more agents suitable for the treatment of the condition, disease or disorder.

Examples of the indications that may be treated by the compounds disclosed herein include but are not limited to metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout, as well as diseases of the central nervous system, such as Alzheimer's disease and multiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinson disease, lung disease, such as asthma and COPD and pulmonary idiopathic fibrosis, liver disease, such as NASH syndrome, viral hepatitis and cirrhosis, pancreatic disease, such as acute and chronic pancreatitis, kidney disease, such as acute and chronic kidney injury, intestinal disease such as Crohn's disease and Ulcerative Colitis, skin disease such as psoriasis, musculoskeletal disease such as scleroderma, vessel disorders, such as giant cell arteritis, disorders of the bones, such as osteoarthritis, osteoporosis and osteopetrosis disorders, eye disease, such as glaucoma and macular degeneration, diseases caused by viral infection such as HIV and AIDS, autoimmune diseases such as rheumatoid arthritis, systemic Lupus erythematosus, autoimmune thyroiditis; Addison's disease, and pernicious anemia, cancer and aging.

The methods can further include identifying the subject.

Other embodiments include those described in the Detailed Description and/or in the claims.

Additional Definitions

To facilitate understanding of the disclosure set forth herein, a number of additional terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well-known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Each of the patents, applications, published applications, and other publications that are mentioned throughout the specification, each of the applications from which this application claims priority, and any attached appendices, are incorporated herein by reference in their entireties. In case of conflict between the present specification and any subject matter incorporated by reference herein, the present specification, including definitions, will control.

As used herein, the term “NLRP1/3” is meant to include, without limitation, nucleic acids, polynucleotides, oligonucleotides, sense and antisense polynucleotide strands, complementary sequences, peptides, polypeptides, proteins, homologous and/or orthologous NLRP molecules, isoforms, precursors, mutants, variants, derivatives, splice variants, alleles, different species, and active fragments thereof.

The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

“API” refers to an active pharmaceutical ingredient.

The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a chemical entity (e.g., a compound exhibiting activity as a modulator of NLRP1/3 or a pharmaceutically acceptable salt and/or hydrate and/or cocrystal thereof) being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.

The term “excipient” or “pharmaceutically acceptable excipient” means a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, carrier, solvent, or encapsulating material. In one embodiment, each component is “pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed.; Lippincott Williams & Wilkins: Philade/lphia, Pa., 2005; Handbook of Pharmaceutical Excipients, 6th ed.; Rowe et al., Eds.; The Pharmaceutical Press and the American Pharmaceutical Association: 2009; Handbook of Pharmaceutical Additives, 3rd ed.; Ash and Ash Eds.; Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, 2nd ed.; Gibson Ed.; CRC Press LLC: Boca Raton, Fla., 2009.

The term “pharmaceutically acceptable salt” may refer to pharmaceutically acceptable addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids. In certain instances, pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. The term “pharmaceutically acceptable salt” may also refer to pharmaceutically acceptable addition salts prepared by reacting a compound having an acidic group with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined. The pharmacologically acceptable salt s not specifically limited as far as it can be used in medicaments. Examples of a salt that the compounds described hereinform with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt. The salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid:organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.

The term “pharmaceutical composition” refers to a mixture of a compound described herein with other chemical components (referred to collectively herein as “excipients”), such as carriers, stabilizers, diluents, dispersing agents, suspending agents, and/or thickening agents. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: rectal, oral, intravenous, aerosol, parenteral, ophthalmic, pulmonary, and topical administration.

The term “subject” refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.

The terms “treat,” “treating,” and “treatment,” in the context of treating a disease or disorder, are meant to include alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.

The terms “hydrogen” and “H” are used interchangeably herein.

The term “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I).

The term “alkyl” refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms. For example, C₁₋₁₀ indicates that the group may have from 1 to 10 (inclusive) carbon atoms in it. Non-limiting examples include methyl, ethyl, iso-propyl, tert-butyl, n-hexyl.

The term “haloalkyl” refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo.

The term “alkoxy” refers to an —O-alkyl radical (e.g., —OCH₃).

The term “carbocyclic ring” as used herein includes an aromatic or nonaromatic cyclic hydrocarbon group having 3 to 10 carbons, such as 3 to 8 carbons, such as 3 to 7 carbons, which may be optionally substituted. Examples of carbocyclic rings include five-membered, six-membered, and seven-membered carbocyclic rings.

The term “heterocyclic ring” refers to an aromatic or nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocyclic rings include five-membered, six-membered, and seven-membered heterocyclic rings.

The term “cycloalkyl” as used herein includes a nonaromatic cyclic hydrocarbon radical having 3 to 10 carbons, such as 3 to 8 carbons, such as 3 to 7 carbons, wherein the cycloalkyl group which may be optionally substituted. Examples of cycloalkyls include five-membered, six-membered, and seven-membered rings. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.

The term “heterocycloalkyl” refers to an aromatic or nonaromatic 5-8 membered monocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ring system radical having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selected from O, N, or S (e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, or S if monocyclic, bicyclic, or tricyclic, respectively), wherein 0, 1, 2 or 3 atoms of each ring may be substituted by a substituent. Examples of heterocycloalkyls include five-membered, six-membered, and seven-membered heterocyclic rings. Examples include piperazinyl, pyrrolidinyl, dioxanyl, morpholinyl, tetrahydrofuranyl, and the like.

The term “hydroxy” refers to an OH group.

The term “amino” refers to an NH₂ group.

The term “oxo” refers to O. By way of example, substitution of a CH₂ a group with oxo gives a C═O group.

As used herein, a curved line connecting two atoms indicates a chain of length as specified by the recited number or number range. For example, a chain connecting an atom “Atom 1” to an atomo “Atom 2” may be depicted as

where the number outside the parenthetical indicates the number or range of numbers in the chain.

In addition, atoms making up the compounds of the present embodiments are intended to include all isotopic forms of such atoms. Isotopes, as used herein, include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium, and isotopes of carbon include ¹³C and ¹⁴C.

The details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features and advantages of the invention will be apparent from the description and drawings, and from the claims.

DETAILED DESCRIPTION

In some embodiments, provided herein is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O; -   or when X¹ is NH, X¹ and R² taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   or when X¹ is NH, X¹ and R⁴ taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; -   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl; -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A, -   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B, -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B, -   wherein ring A is

-   and ring B is

-   wherein -   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆     cycloalkyl and C₃-C₆ heterocycloalkyl; -   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆     heterocycloalkyl, R⁹ is optionally substituted with one or more     substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,     and CONR¹¹R¹²; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   or two R¹⁰ taken together with the carbon connecting them form a     three-to-eight-membered heterocyclic ring containing 1 or 2     heteroatoms independently selected from O, N, and S, or a     three-membered, six-membered, seven-membered, or eight-membered     carbocyclic ring, wherein the heterocyclic ring or carbocyclic ring     is optionally substituted with one or more substituents each     independently selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹²,     oxo, and ═NR¹³; -   R¹³ is C₁-C₆ alkyl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen, C₁-C₆ alkyl, CO₂R¹⁵ and CONR¹⁷R¹⁸; -   R¹⁵ is C₁-C₆ alkyl; -   each of R¹⁷ and R¹⁸ at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl; -   each R¹⁶ is the same or different and is selected from H, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, provided herein is a compound of Formula I

-   or a pharmaceutically acceptable salt thereof, wherein: -   X¹ is NH or O; -   or when X¹ is NH, X¹ and R² taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   or when X¹ is NH, X¹ and R⁴ taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; -   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl; -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A, -   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B, -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B, -   wherein ring A is

and ring B is

-   wherein -   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆     cycloalkyl and C₃-C₆ heterocycloalkyl; -   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆     heterocycloalkyl, R⁹ is optionally substituted with one or more     substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,     and CONR¹¹R¹²; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   R¹³ is C₁-C₆ alkyl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen, C₁-C₆ alkyl, CO₂R¹⁵ and CONR¹⁷R¹⁸; -   R¹⁵ is C₁-C₆ alkyl; -   each of R¹⁷ and R¹⁸ at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl; -   each R¹⁶ is the same or different and is selected from H, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, provided herein is a compound of Formula I

-   or a pharmaceutically acceptable salt thereof, wherein: -   X¹ is NH or O; -   or when X¹ is NH, X¹ and R² taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   or when X¹ is NH, X¹ and R⁴ taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; -   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl; -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A, -   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B, -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B, -   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆     cycloalkyl and C₃-C₆ heterocycloalkyl; -   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆     heterocycloalkyl, R⁹ is optionally substituted with one or more     substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,     and CONR¹¹R¹²; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   R¹³ is C₁-C₆ alkyl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen, C₁-C₆ alkyl, -   CO₂R¹⁵ and CONR¹⁷R¹⁸; -   R¹⁵ is C₁-C₆ alkyl; -   each of R¹⁷ and R¹⁸ at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl; each R¹⁶ is the same or different and     is selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and     ═NR¹³; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, provided herein is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O; -   or when X¹ is NH, X¹ and R² taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; -   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl; -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A, -   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B, -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B, -   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH), C(R¹⁰)₂NR¹¹R¹², C₃-C₆     cycloalkyl and C₃-C₆ heterocycloalkyl; -   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆     heterocycloalkyl, R⁹ is optionally substituted with one or more     substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,     and CONR¹¹R¹²; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   R¹³ is C₁-C₆ alkyl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen, C₁-C₆ alkyl, CO₂R¹⁵ and CONR¹⁷R¹⁸; -   R¹⁵ is C₁-C₆ alkyl; -   each of R¹⁷ and R¹⁸ at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl; each R¹⁶ is the same or different and     is selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹²; oxo, and     ═NR¹³; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, provided herein is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O; -   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; -   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl; -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A, -   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B, -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B, -   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆     cycloalkyl and C₃-C₆ heterocycloalkyl; -   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆     heterocycloalkyl, R⁹ is optionally substituted with one or more     substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,     and CONR¹¹R¹²; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   each of R¹¹, R¹² and R¹³ at each occurrence is independently     selected from hydrogen and C₁-C₆ alkyl; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, provided herein is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O; -   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; -   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A, -   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B, -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B, -   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆     cycloalkyl and C₃-C₆ heterocycloalkyl; -   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆     heterocycloalkyl, R⁹ is optionally substituted with one or more     substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,     and CONR¹¹R¹²; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   each of R¹¹, R¹² and R¹³ at each occurrence is independently     selected from hydrogen and C₁-C₆ alkyl; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, provided herein is a compound of Formula II

wherein the compound of Formula II is selected from

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O; -   or when X¹ is NH, X¹ and R² taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   or when X¹ is NH, X¹ and R⁴ taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   Y is N or CR⁸; -   Y′ is N or CR^(8′); -   Z is N or CH; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, C₁-C₆ haloalkoxy, and C₁-C₆     haloalkyl; -   R^(8′) is selected from H, CN, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; -   R^(8″) is selected from CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; -   R^(8′″) is selected from H, CN, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl,     CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; -   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R³ is hydrogen, CN, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆     alkyl optionally substituted with hydroxy; -   R^(3′) is hydrogen, CN, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or     C₁-C₆ alkyl optionally substituted with hydroxy; -   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁵ is hydrogen, CN, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆     alkyl optionally substituted with hydroxy; -   R^(5′) is hydrogen, CN, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or     C₁-C₆ alkyl optionally substituted with hydroxy; -   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl; -   or R² and R³, if both present, taken together with the carbons     connecting them form a four-membered to seven-membered ring A, -   or R⁴ and R⁵, if both present, taken together with the carbons     connecting them form a four-membered to seven-membered ring B, -   or R² and R³, if both present, taken together with the carbons     connecting them form a four-membered to seven-membered ring A and R⁴     and R⁵, if both present, taken together with the carbons connecting     them form a four-membered to seven-membered ring B, -   R^(2″) and R^(3″), if both present, taken together with the carbons     connecting them form a four-membered to seven-membered ring A and     R^(4″) and R^(5″), if both present, taken together with the carbons     connecting them form a four-membered to seven-membered ring B, -   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from CN, Cl, C(R¹⁰)₂OH, or F; -   R^(1′) is selected from C(O)C₁-C₆ alkyl or CO₂C₁-C₆ alkyl; -   R^(1″) is selected from H or C(R¹⁰)₂OH; -   R¹⁴ is selected from H, CN, Cl, or F; -   R^(14′) is selected from CN or F; -   R^(14″) is selected from CN, Cl, or F; -   R⁹ is selected from H, C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)²NR¹¹R¹², C₃-C₆     cycloalkyl, pyridyl, and morpholinyl; -   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆     heterocycloalkyl, R⁹ is optionally substituted with one or more     substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,     and CONR¹¹R¹²; -   R^(9′) is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹²,     C₃-C₆ cycloalkyl, phenyl, pyridyl, and morpholinyl -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   or two R¹⁰ taken together with the carbon connecting them form a     three-to-eight-membered heterocyclic ring containing 1 or 2     heteroatoms independently selected from O, N, and S, or a     three-membered, six-membered, seven-membered, or eight-membered     carbocyclic ring, wherein the heterocyclic ring or carbocyclic ring     is optionally substituted with one or more substituents each     independently selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹²,     oxo, and ═NR¹³; -   R¹³ is C₁-C₆ alkyl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen, C₁-C₆ alkyl, CO₂R¹⁵ and CONR¹⁷R¹⁸; -   R¹⁵ is C₁-C₆ alkyl; -   each of R¹⁷ and R¹⁸ at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl; -   each R¹⁶ is the same or different and is selected from H, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³.

In some embodiments, provided herein is a compound of Formula II

wherein the compound of Formula II is selected from

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH; -   Y is CR⁸; -   Y′ is CR^(8′); -   Z is N or CH; -   R⁸ is selected from H, CN, Cl, F, and CONR¹¹R¹²; -   R^(8′) is H; -   R^(8″) is selected from CN or F; -   R^(8′″) is selected from H, CN, CO₂C₁-C₆ alkyl, or CONR¹¹R¹²; -   R² is C₁-C₆ alkyl; -   R³ is hydrogen or halo; -   R^(3′) is hydrogen or halo; -   R⁴ is C₁-C₆ alkyl; -   R⁵ is hydrogen; -   R^(5′) is hydrogen; -   provided that at least one of R², R³, R⁴, and R⁵ is not hydrogen,     and that R² and R⁴ are not both hydroxymethyl; -   or R² and R³, if both present, taken together with the carbons     connecting them form a four-membered to seven-membered ring A, -   or R⁴ and R⁵, if both present, taken together with the carbons     connecting them form a four-membered to seven-membered ring B, -   or R² and R³, if both present, taken together with the carbons     connecting them form a four-membered to seven-membered ring A and R⁴     and R⁵, if both present, taken together with the carbons connecting     them form a four-membered to seven-membered ring B, -   R^(2″) and R^(3″), if both present, taken together with the carbons     connecting them form a four-membered to seven-membered ring A and     R^(4″) and R^(5″), if both present, taken together with the carbons     connecting them form a four-membered to seven-membered ring B, -   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring; -   n1 is 3; -   m1 is 1; -   wherein ring B is a carbocyclic ring; -   n2 is 3; -   m2 is 1; -   wherein each R⁶ in each ring is the same or different and is     selected from H; -   R¹ is selected from CN, Cl, C(R¹⁰)₂OH, or F; -   R^(1″) is selected from H or C(R¹⁰)₂OH; -   R¹⁴ is selected from H or F; -   R^(14″) is F; -   R^(9′) is selected from C(R¹⁰)₂OH, C₃-C₆ cycloalkyl, phenyl,     pyridyl, or morpholinyl each R¹⁰ is the same and is C₁-C₆ alkyl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen, C₁-C₆ alkyl, CO₂R¹⁵ and CONR¹⁷R¹⁸; -   R¹⁵ is C₁-C₆ alkyl; -   each of R¹⁷ and R¹⁸ at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl.

In some embodiments the variables shown in the formulae herein are as follows:

The group X¹

In some embodiments, X¹ is NH.

In some embodiments, X¹ is O

In some embodiments, X¹ and R² taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R¹⁶.

In some embodiments, X¹ and R⁴ taken together with the atoms connecting them form a four-to-seven-membered heterocyclic ring optionally substituted with one or more R¹⁶.

In some embodiments, X¹ and R² taken together with the atoms connecting them form a four-to-seven-membered ring C of the formula

wherein q1 is 0, 1, 2 or 3; A1 is N; A2 is O, NH, or CH₂, provided that A1 and A2 are not both heteroatoms; and ring C is optionally substituted with 1 to 8 R¹⁶.

In some embodiments of ring C, A1 is N and A2 is CH₂.

In some embodiments of ring C, R¹⁶ is H.

In some embodiments, ring C is a heterocyclic ring containing one heteroatom selected from O, N and S.

In some embodiments, ring C is a heterocyclic ring containing two heteroatoms each independently selected from O, N and S.

The groups Y and Y′

In some embodiments of one or more formulae herein, Y is CR⁸.

In some embodiments of one or more formulae herein, Y is N.

In some embodiments of one or more formulae herein, Y′ is CR^(8′).

In some embodiments of one or more formulae herein, Y′ is N.

The group Z

In some embodiments of one or more formulae herein, Z is N or CH.

In some embodiments of one or more formulae herein, Z is N.

In some embodiments of one or more formulae herein, Z is CH.

The groups R², R⁴, R³ and R⁵

In some embodiments of one or more formulae herein, R² is hydrogen.

In some embodiments of one or more formulae herein, R² is C₁-C₆ alkoxy.

In some embodiments of one or more formulae herein, R² is methoxy.

In some embodiments of one or more formulae herein, R² is halo.

In some embodiments of one or more formulae herein, R² is C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R² is CF₃.

In some embodiments of one or more formulae herein, R² is C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R² is isopropyl.

In some embodiments of one or more formulae herein, R² is methyl.

In some embodiments of one or more formulae herein, R³ is hydrogen.

In some embodiments of one or more formulae herein, R³ is CN.

In some embodiments of one or more formulae herein, R³ is C₁-C₆ alkoxy.

In some embodiments of one or more formulae herein, R³ is methoxy.

In some embodiments of one or more formulae herein, R³ is halo.

In some embodiments of one or more formulae herein, R³ is C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R³ is CF₃.

In some embodiments of one or more formulae herein, R³ is C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R³ is isopropyl.

In some embodiments of one or more formulae herein, R³ is methyl.

In some embodiments of one or more formulae herein, R⁴ is hydrogen.

In some embodiments of one or more formulae herein, R⁴ is C₁-C₆ alkoxy.

In some embodiments of one or more formulae herein, R⁴ is methoxy.

In some embodiments of one or more formulae herein, R⁴ is halo.

In some embodiments of one or more formulae herein, R⁴ is C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R⁴ is CF₃.

In some embodiments of one or more formulae herein, R⁴ is C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R⁴ is isopropyl.

In some embodiments of one or more formulae herein, R⁴ is methyl.

In some embodiments of one or more formulae herein, R⁵ is hydrogen.

In some embodiments of one or more formulae herein, R⁵ is CN.

In some embodiments of one or more formulae herein, R⁵ is C₁-C₆ alkoxy.

In some embodiments of one or more formulae herein, R⁵ is methoxy.

In some embodiments of one or more formulae herein, R⁵ is halo.

In some embodiments of one or more formulae herein, R⁵ is C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R⁵ is CF₃.

In some embodiments of one or more formulae herein, R⁵ is C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R⁵ is isopropyl.

In some embodiments of one or more formulae herein, R⁵ is methyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ is hydrogen.

In some embodiments of one or more formulae herein, each of R² and R⁴ is C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R² and R⁴ is isopropyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ is t-butyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ is methyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ is hydroxymethyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ is hydrogen.

In some embodiments of one or more formulae herein, each of R³ and R⁵ is C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R³ and R⁵ is isopropyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ is t-butyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ is methyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ is hydroxymethyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ is hydrogen and each of R² and R⁴ is C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R³ and R⁵ is hydrogen and each of R² and R⁴ is isopropyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ is hydrogen and each of R² and R⁴ is t-butyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ is hydrogen and each of R² and R⁴ is methyl.

In some embodiments of one or more formulae herein, each of R³ and R⁵ is hydrogen and each of R² and R⁴ is hydroxymethyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ is hydrogen and each of R³ and R⁵ is C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R² and R⁴ is hydrogen and each of R³ and R⁵ is isopropyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ is hydrogen and each of R³ and R⁵ is t-butyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ is hydrogen and each of R³ and R⁵ is methyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ is hydrogen and each of R³ and R⁵ is hydroxymethyl.

In some embodiments of one or more formulae herein, R² and R³ taken together with the carbons connecting them form ring A.

In some embodiments of one or more formulae herein, R⁴ and R⁵ taken together with the carbons connecting them form ring B.

In some embodiments of one or more formulae herein, R² and R³ taken together with the carbons connecting them form ring A and R⁴ and R⁵ taken together with the carbons connecting them form ring B.

In some embodiments of one or more formulae herein, R² and R³, taken together with the carbons connecting them form a five membered ring A and R⁴ and R⁵, taken together with the carbons connecting them form a five-membered ring B, wherein ring A is a saturated carbocyclic ring, ring B is a saturated carbocyclic ring, n1 is 3, n2 is 3, and R⁶ is H.

The groups R^(3′) and R^(5′)

In some embodiments of one or more formulae herein, R^(3′) is hydrogen.

In some embodiments of one or more formulae herein, R^(3′) is CN.

In some embodiments of one or more formulae herein, R^(3′) is C₁-C₆ alkoxy.

In some embodiments of one or more formulae herein, R^(3′) is methoxy.

In some embodiments of one or more formulae herein, R^(3′) is halo.

In some embodiments of one or more formulae herein, R^(3′) is F.

In some embodiments of one or more formulae herein, R^(3′) is C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R^(3′) is CF₃.

In some embodiments of one or more formulae herein, R^(3′) is C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R^(3′) is isopropyl.

In some embodiments of one or more formulae herein, R^(3′) is methyl.

In some embodiments of one or more formulae herein, R^(5′) is hydrogen.

In some embodiments of one or more formulae herein, R^(5′) is CN.

In some embodiments of one or more formulae herein, R^(5′) is C₁-C₆ alkoxy.

In some embodiments of one or more formulae herein, R^(5′) is methoxy.

In some embodiments of one or more formulae herein, R^(5′) is halo.

In some embodiments of one or more formulae herein, R^(5′) is F.

In some embodiments of one or more formulae herein, R⁵ is C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R^(5′) is CF₃.

In some embodiments of one or more formulae herein, R^(5′) is C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, R^(5′) is isopropyl.

In some embodiments of one or more formulae herein, R^(5′) is methyl.

In some embodiments of one or more formulae herein, each of R^(3′) and R^(5′) is hydrogen.

In some embodiments of one or more formulae herein, each of R^(3′) and R^(5′) is C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R^(3′) and R^(5′) is isopropyl.

In some embodiments of one or more formulae herein, each of R^(3′) and R^(5′) is t-butyl.

In some embodiments of one or more formulae herein, each of R^(3′) and R^(5′) is methyl.

In some embodiments of one or more formulae herein, each of R^(3′) and R^(5′) is hydroxymethyl.

In some embodiments of one or more formulae herein, each of R^(3′) and R^(5′) is hydrogen and each of R² and R⁴ is C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R^(3′) and R^(5′) is hydrogen and each of R² and R⁴ is isopropyl.

In some embodiments of one or more formulae herein, each of R^(3′) and R^(5′) is hydrogen and each of R² and R⁴ is t-butyl.

In some embodiments of one or more formulae herein, each of R^(3′) and R^(5′) is hydrogen and each of R² and R⁴ is methyl.

In some embodiments of one or more formulae herein, each of R^(3′) and R^(5′) is hydrogen and each of R² and R⁴ is hydroxymethyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ is hydrogen and each of R^(3′) and R^(5′) is C₁-C₆ alkyl optionally substituted with hydroxy.

In some embodiments of one or more formulae herein, each of R² and R⁴ is hydrogen and each of R^(3′) and R^(5′) is isopropyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ is hydrogen and each of R^(3′) and R^(5′) is t-butyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ is hydrogen and each of R^(3′) and R^(5′) is methyl.

In some embodiments of one or more formulae herein, each of R² and R⁴ is hydrogen and each of R^(3′) and R^(5′) is hydroxymethyl.

The groups R^(2″), R^(4″), R^(3″) and R^(5″)

In some embodiments of one or more formulae herein, R^(2″) and R^(3″) taken together with the carbons connecting them form ring A and R^(4″) and R^(5″) taken together with the carbons connecting them form ring B.

In some embodiments of one or more formulae herein, R^(2″) and R³″, taken together with the carbons connecting them form a five membered ring A and R^(4″) and R^(5″), taken together with the carbons connecting them form a five-membered ring B wherein ring A is a saturated carbocyclic ring and ring B is a saturated carbocyclic ring, and wherein n1 is 3, n2 is 3, and R⁶ is H.

Rings A and B

In some embodiments of one or more formulae herein, ring A is a carbocyclic ring.

In some embodiments of one or more formulae herein, ring A is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments of one or more formulae herein, ring B is a carbocyclic ring.

In some embodiments of one or more formulae herein, ring B is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments, ring A is a carbocyclic ring and n1 is 3.

In some embodiments, ring A is a carbocyclic ring and n1 is 4.

In some embodiments, ring A is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n1 is 3.

In some embodiments, ring A is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n1 is 4.

In some embodiments, ring B is a carbocyclic ring and n2 is 3.

In some embodiments, ring B is a carbocyclic ring and n2 is 4.

In some embodiments, ring B is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n2 is 3.

In some embodiments, ring B is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n2 is 4.

In some embodiments, ring A is the same as ring B.

In some embodiments, ring A is

In some embodiments, ring B is

In some embodiments, ring B is

and is the same as ring A.

In some embodiments, ring A is

In some embodiments, ring B is

and is the same as ring A.

In some embodiments, ring A is a heterocyclic ring of the formula

In some embodiments, ring A is a heterocyclic ring of the formula

The Groups R⁶ and R⁷ and the Variables n1, n2, m1 and m2 in Ring A and Ring B

In some embodiments of one or more formulae herein, R⁶ is H.

In some embodiments of one or more formulae herein, R⁶ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R⁶ is C₁-C₆ alkoxy.

In some embodiments of one or more formulae herein, R⁶ is methoxy.

In some embodiments of one or more formulae herein, R⁶ is NR¹¹R¹².

In some embodiments of one or more formulae herein, R⁶ is oxo.

In some embodiments of one or more formulae herein, R⁶ is ═NR¹³.

In some embodiments of one or more formulae herein, n1 is 2.

In some embodiments of one or more formulae herein, n1 is 3.

In some embodiments of one or more formulae herein, n1 is 4.

In some embodiments of one or more formulae herein, n1 is 5.

In some embodiments of one or more formulae herein, n2 is 2.

In some embodiments of one or more formulae herein, n2 is 3.

In some embodiments of one or more formulae herein, n2 is 4.

In some embodiments of one or more formulae herein, n2 is 5.

In some embodiments of one or more formulae herein, m1 is 1.

In some embodiments of one or more formulae herein, m1 is 2.

In some embodiments of one or more formulae herein, m1 is 3.

In some embodiments of one or more formulae herein, m1 is 4.

In some embodiments of one or more formulae herein, m2 is 1.

In some embodiments of one or more formulae herein, m2 is 2.

In some embodiments of one or more formulae herein, m2 is 3.

In some embodiments of one or more formulae herein, m2 is 4.

In some embodiments of one or more formulae herein, two R⁶ taken together with the atom or atoms connecting them form a 3-to-8-membered carbocyclic or saturated heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments of one or more formulae herein, each R⁶ in each ring is H.

In some embodiments of one or more formulae herein, each R⁶ in each ring is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, each R⁷ in each ring is H.

In some embodiments of one or more formulae herein, each R⁷ in each ring is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, each R⁶ in each ring is H and each R⁷ in each ring is H.

In some embodiments of one or more formulae herein, each R⁶ in each ring is H and each R⁷ in each ring is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, each R⁶ in each ring is C₁-C₆ alkyl and each R⁷ in each ring is H.

In some embodiments of one or more formulae herein, each R⁶ in each ring is C₁-C₆ alkyl and each R⁷ in each ring is C₁-C₆ alkyl.

The Ring E

In some embodiments of one or more formulae herein,

In some embodiments of one or more formulae herein,

In some embodiments of one or more formulae herein,

In some embodiments of one or more formulae herein,

In some embodiments of one or more formulae herein,

The Groups R⁸, R^(8′), R^(8″), and R^(8′″)

In some embodiments of one or more formulae herein, R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, C₁-C₆ haloalkoxy, and C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂.

In some embodiments of one or more formulae herein, R⁸ is H.

In some embodiments of one or more formulae herein, R⁸ is CN.

In some embodiments of one or more formulae herein, R⁸ is Cl.

In some embodiments of one or more formulae herein, R⁸ is F.

In some embodiments of one or more formulae herein, R⁸ is CO₂C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R⁸ is COCH₃.

In some embodiments of one or more formulae herein, R⁸ is CO₂C₃-C₈ cycloalkyl.

In some embodiments of one or more formulae herein, R⁸ is CONH₂.

In some embodiments of one or more formulae herein, R⁸ is CONR¹¹R¹².

In some embodiments of one or more formulae herein, R⁸ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R⁸ is C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R⁸ is CF₃.

In some embodiments of one or more formulae herein, R⁸ is haloalkoxy.

In some embodiments of one or more formulae herein, R⁸ is OCF₂.

In some embodiments of one or more formulae herein, R^(8′) is selected from H, CN, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R^(8′) is selected from H, CN, F, CO₂C₁-C₆ alkyl and CONH₂.

In some embodiments of one or more formulae herein, R^(8′) is H.

In some embodiments of one or more formulae herein, R^(8′) is CN.

In some embodiments of one or more formulae herein, R^(8′) is F.

In some embodiments of one or more formulae herein, R^(8′) is CO₂C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R^(8′) is COCH₃.

In some embodiments of one or more formulae herein, R^(8′) is CO₂C₃-C₈ cycloalkyl.

In some embodiments of one or more formulae herein, R^(8′) is CONH₂.

In some embodiments of one or more formulae herein, R^(8′) is CONR¹¹R¹².

In some embodiments of one or more formulae herein, R^(8′) is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R^(8′) is C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R^(8′) is CF₃.

In some embodiments of one or more formulae herein, R^(8′) is selected from CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R^(8″) is selected from CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂.

In some embodiments of one or more formulae herein, R^(8″) is CN.

In some embodiments of one or more formulae herein, R^(8″) is Cl.

In some embodiments of one or more formulae herein, R^(8″) is F.

In some embodiments of one or more formulae herein, R^(8″) is CO₂C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R^(8″) is COCH₃.

In some embodiments of one or more formulae herein, R^(8″) is CO₂C₃-C₈ cycloalkyl.

In some embodiments of one or more formulae herein, R^(8″) is CONH₂.

In some embodiments of one or more formulae herein, R^(8″) is CONR¹¹R¹².

In some embodiments of one or more formulae herein, R^(8″) is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R^(8″) is C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R^(8″) is CF₃.

In some embodiments of one or more formulae herein, R^(8″) is selected from H, CN, CO₂C₁-C₆ alkyl, CO₂C₃-C₈ cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R^(8′″) is selected from H, CN, CO₂C₁-C₆ alkyl and CONH₂.

In some embodiments of one or more formulae herein, R^(8′″) is H.

In some embodiments of one or more formulae herein, R^(8′″) is CN.

In some embodiments of one or more formulae herein, R^(8′″) is CO₂C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R^(8′″) is COCH₃.

In some embodiments of one or more formulae herein, R^(8′″) is CO₂C₃-C₈ cycloalkyl.

In some embodiments of one or more formulae herein, R^(8′″) is CONH₂.

In some embodiments of one or more formulae herein, R^(8′″) is CONR¹¹R¹².

In some embodiments of one or more formulae herein, R^(8′″) is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R^(8′″) is C₁-C₆ haloalkyl.

In some embodiments of one or more formulae herein, R^(8′″) is CF₃.

The Groups R¹, R^(1′), and R^(1″)

In some embodiments of one or more formulae herein, R¹ is selected from CN, Cl, C(R¹⁰)₂OH, or F;

In some embodiments of one or more formulae herein, R¹ is selected from CN, Cl, or F;

In some embodiments of one or more formulae herein, R¹ is selected from Cl, C(R¹⁰)₂OH, or F;

In some embodiments of one or more formulae herein, R¹ is selected from CN, C(R¹⁰)₂OH, or F;

In some embodiments of one or more formulae herein, R¹ is selected from CN, Cl, or C(R¹⁰)₂OH;

In some embodiments of one or more formulae herein, R¹ is selected from C(R¹⁰)₂OH or F;

In some embodiments of one or more formulae herein, R¹ is selected from Cl or C(R¹⁰)₂OH;

In some embodiments of one or more formulae herein, R¹ is selected from CN or C(R¹⁰)₂OH;

In some embodiments of one or more formulae herein, R¹ is selected from CN or Cl;

In some embodiments of one or more formulae herein, R¹ is selected from CN or F;

In some embodiments of one or more formulae herein, R¹ is selected from Cl or F;

In some embodiments of one or more formulae herein, R¹ is CN.

In some embodiments of one or more formulae herein, R¹ is Cl.

In some embodiments of one or more formulae herein, R¹ is C(R¹⁰)₂OH.

In some embodiments of one or more formulae herein, R¹ is 2-hydroxy-2-propyl.

In some embodiments of one or more formulae herein, R¹ is hydroxymethyl.

In some embodiments of one or more formulae herein, R¹ is F.

In some embodiments of one or more formulae herein, R^(1′) is C(O)C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R^(1′) is CO₂C₁-C₆ alkyl;

In some embodiments of one or more formulae herein, R^(1′) is acetyl.

In some embodiments of one or more formulae herein, R^(1′) is 1-propanoyl.

In some embodiments of one or more formulae herein, R^(1′) is 2-propanoyl.

In some embodiments of one or more formulae herein, R^(1′) is 1-butanoyl.

In some embodiments of one or more formulae herein, R^(1′) is 2-butanoyl.

In some embodiments of one or more formulae herein, R^(1′) is t-butanoyl.

In some embodiments of one or more formulae herein, R^(1″) is selected from H or C(R¹⁰)₂OH.

In some embodiments of one or more formulae herein, R^(1″) is selected from H.

In some embodiments of one or more formulae herein, R^(1″) is selected from C(R¹⁰)₂OH.

The Groups R¹⁴, R^(14′), and R^(14″)

In some embodiments of one or more formulae herein, R¹⁴ is selected from H, CN, Cl, or F.

In some embodiments of one or more formulae herein, R¹⁴ is selected from CN, Cl, or F.

In some embodiments of one or more formulae herein, R¹⁴ is selected from H, CN, or F.

In some embodiments of one or more formulae herein, R¹⁴ is selected from H, CN, or Cl.

In some embodiments of one or more formulae herein, R¹⁴ is selected from H, CN, or Cl.

In some embodiments of one or more formulae herein, R¹⁴ is selected from H, Cl, or F.

In some embodiments of one or more formulae herein, R¹⁴ is selected from Cl or F.

In some embodiments of one or more formulae herein, R¹⁴ is H.

In some embodiments of one or more formulae herein, R¹⁴ is CN.

In some embodiments of one or more formulae herein, R¹⁴ is Cl.

In some embodiments of one or more formulae herein, R¹⁴ is F.

In some embodiments of one or more formulae herein, R^(14′) is selected from CN or F.

In some embodiments of one or more formulae herein, R^(14′) is CN.

In some embodiments of one or more formulae herein, R^(14′) is F.

In some embodiments of one or more formulae herein, R^(14″) is selected from CN, Cl, or F.

In some embodiments of one or more formulae herein, R^(14″) is selected from CN or F.

In some embodiments of one or more formulae herein, R^(14″) is CN.

In some embodiments of one or more formulae herein, R^(14″) is Cl.

In some embodiments of one or more formulae herein, R^(14″) is F.

The Groups R⁹ and R^(9′)

In some embodiments of one or more formulae herein, R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)²NR¹¹R¹², C₃-C₆ cycloalkyl and C₃-C₆ heterocycloalkyl.

In some embodiments of one or more formulae herein, R⁹ is selected from H, C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)²NR¹¹R¹², C₃-C₆ cycloalkyl, phenyl, pyridyl, and morpholinyl; wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆ heterocycloalkyl, R⁹ is optionally substituted with one or more substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl, and CONR¹¹R¹².

In some embodiments of one or more formulae herein, R⁹ is selected from H, C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)²NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl, and morpholinyl; wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆ heterocycloalkyl, R⁹ is optionally substituted with one or more substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl, and CONR¹¹R¹².

In some embodiments of one or more formulae herein, R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)²NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R⁹ is selected from H, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹², C₃-C₆ cycloalkyl, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R⁹ is selected from H, C₁-C₆ alkyl, C(R¹⁰)₂NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R⁹ is selected from H, C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)²NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R⁹ is selected from C(R¹⁰)₂OH, C₃-C₆ cycloalkyl, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R⁹ is selected from C(R¹⁰)₂OH, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R⁹ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R⁹ is methyl.

In some embodiments of one or more formulae herein, R⁹ is ethyl.

In some embodiments of one or more formulae herein, R⁹ is propyl.

In some embodiments of one or more formulae herein, R⁹ is butyl.

In some embodiments of one or more formulae herein, R⁹ is C(R¹⁰)₂OH.

In some embodiments of one or more formulae herein, R⁹ is 2-hydroxy-2-propyl.

In some embodiments of one or more formulae herein, R⁹ is hydroxymethyl.

In some embodiments of one or more formulae herein, R⁹ is C(R¹⁰)₂NR¹¹R¹².

In some embodiments of one or more formulae herein, R⁹ is C₃-C₆ cycloalkyl.

In some embodiments of one or more formulae herein, R⁹ is cyclopropyl.

In some embodiments of one or more formulae herein, R⁹ is cyclobutyl.

In some embodiments of one or more formulae herein, R⁹ is cyclopentyl.

In some embodiments of one or more formulae herein, R⁹ is cyclohexyl.

In some embodiments of one or more formulae herein, R⁹ is phenyl.

In some embodiments of one or more formulae herein, R⁹ is C₃-C₆ heterocycloalkyl.

In some embodiments of one or more formulae herein, R⁹ is selected from morpholinyl or pyridyl.

In some embodiments of one or more formulae herein, R⁹ is morpholinyl.

In some embodiments of one or more formulae herein, R⁹ is N-morpholinyl.

In some embodiments of one or more formulae herein, R⁹ is pyridyl.

In some embodiments of one or more formulae herein, R⁹ is 2-pyridyl.

In some embodiments of one or more formulae herein, R⁹ is 3-pyridyl.

In some embodiments of one or more formulae herein, R⁹ is 4-pyridyl.

In some embodiments of one or more formulae herein, R⁹ is H.

In some embodiments of one or more formulae herein, R⁹ is substituted with ═NR¹³.

In some embodiments of one or more formulae herein, R⁹ is substituted with COOC₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R⁹ is substituted with CONR¹¹R¹².

In some embodiments of one or more formulae herein, R^(9′) is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)²NR¹¹R¹², C₃-C₆ cycloalkyl, phenyl, pyridyl, and morpholinyl; wherein, when R^(9′) is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆ heterocycloalkyl, R^(9′) is optionally substituted with one or more substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl, and CONR¹¹R¹²;

In some embodiments of one or more formulae herein, R^(9′) is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is selected from C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is selected from C₁-C₆ alkyl, C(R¹⁰)₂NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆ cycloalkyl, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is selected from C(R¹⁰)₂OH, C₃-C₆ cycloalkyl, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is selected from C(R¹⁰)₂OH, pyridyl, and morpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R^(9′) is methyl.

In some embodiments of one or more formulae herein, R^(9′) is ethyl.

In some embodiments of one or more formulae herein, R^(9′) is propyl.

In some embodiments of one or more formulae herein, R^(9′) is butyl.

In some embodiments of one or more formulae herein, R^(9′) is C(R¹⁰)₂OH.

In some embodiments of one or more formulae herein, R^(9′) is 2-hydroxy-2-propyl.

In some embodiments of one or more formulae herein, R^(9′) is hydroxymethyl.

In some embodiments of one or more formulae herein, R^(9′) is C(R¹⁰)₂NR¹¹R¹².

In some embodiments of one or more formulae herein, R^(9′) is C₃-C₆ cycloalkyl.

In some embodiments of one or more formulae herein, R^(9′) is cyclopropyl.

In some embodiments of one or more formulae herein, R^(9′) is cyclobutyl.

In some embodiments of one or more formulae herein, R^(9′) is cyclopentyl.

In some embodiments of one or more formulae herein, R^(9′) is cyclohexyl.

In some embodiments of one or more formulae herein, R^(9′) is phenyl.

In some embodiments of one or more formulae herein, R^(9′) is C₃-C₆ heterocycloalkyl.

In some embodiments of one or more formulae herein, R^(9′) is selected from morpholinyl or pyridyl.

In some embodiments of one or more formulae herein, R^(9′) is morpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is N-morpholinyl.

In some embodiments of one or more formulae herein, R^(9′) is pyridyl.

In some embodiments of one or more formulae herein, R^(9′) is 2-pyridyl.

In some embodiments of one or more formulae herein, R^(9′) is 3-pyridyl.

In some embodiments of one or more formulae herein, R^(9′) is 4-pyridyl.

In some embodiments of one or more formulae herein, R^(9′) is substituted with ═NR¹³.

In some embodiments of one or more formulae herein, R^(9′) is substituted with COOC₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R^(9′) is substituted with CONR¹¹R¹².

The Group R¹⁰

In some embodiments of one or more formulae herein, each R¹⁰ is H.

In some embodiments of one or more formulae herein, each R¹⁰ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, each R¹⁰ is methyl.

In some embodiments of one or more formulae herein, each R¹⁰ is ethyl.

In some embodiments of one or more formulae herein, two R¹⁰ taken together with the carbon connecting them form a three-to-eight-membered heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S.

In some embodiments of one or more formulae herein, two R¹⁰ taken together with the carbon connecting them form a three-membered, six-membered, seven-membered, or eight-membered carbocyclic ring.

In some embodiments, the heterocyclic ring or carbocyclic ring is optionally substituted with one or more substituents each independently selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³.

In some embodiments of the one or more formulae herein, each R¹⁰ is the same.

The Groups R¹¹ and R¹²

In some embodiments of one or more formulae herein, R¹¹ is hydrogen.

In some embodiments of one or more formulae herein, R¹¹ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R¹¹ is CO₂R¹⁵.

In some embodiments of one or more formulae herein, R¹¹ is CONR¹⁷NR¹⁸.

In some embodiments of one or more formulae herein, R¹² is hydrogen.

In some embodiments of one or more formulae herein, R¹² is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R¹² is CO₂R¹⁵.

In some embodiments of one or more formulae herein, R¹² is CONR¹⁷NR¹⁸.

The Groups R¹³, R¹⁵, R¹⁷ and R¹⁸

In some embodiments of one or more formulae herein, R¹³ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R¹⁵ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R¹⁷ is hydrogen.

In some embodiments of one or more formulae herein, R¹⁷ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R¹⁸ is hydrogen.

In some embodiments of one or more formulae herein, R¹⁸ is C₁-C₆ alkyl.

The Group R¹⁶

In some embodiments of one or more formulae herein, R¹⁶ is hydrogen.

In some embodiments of one or more formulae herein, R¹⁶ is C₁-C₆ alkyl.

In some embodiments of one or more formulae herein, R¹⁶ is C₁-C₆ alkoxy.

In some embodiments of one or more formulae herein, R¹⁶ is NR¹¹R¹².

In some embodiments of one or more formulae herein, R¹⁶ is oxo.

In some embodiments of one or more formulae herein, R¹⁶ is C₁═NR¹³.

Additional Embodiments

In some embodiments of one or more formulae herein:

if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is C₁-C₆ alkyl; R^(H) is H; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments of one or more formulae herein:

if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is C₁-C₆ alkyl; R¹ is H, then R⁸ is not F or Cl.

In some embodiments the compound of any of the formulae herein is not a compound disclosed in any of Examples 1-150 of patent publication WO2001/019390, which are incorporated by reference herein.

In some embodiments the compound of any of the formulae herein is not a compound disclosed in any of Examples 1-130 of patent publication WO 98/32733, which are incorporated by reference herein.

In some embodiments the compound of any of the formulae herein is not a compound disclosed in any of the Examples at [00123] of patent publication WO2016/131098, which are incorporated by reference herein.

In some embodiments, provided herein is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O; -   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂; -   R² is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy; -   R³ is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy; -   R⁴ is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy     and is the same as R²; -   R⁵ is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy     and is the same as R³; -   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl; -   or R² and R³ taken together with the carbons connecting them form a     five-membered ring A and R⁴ and R⁵ taken together with the carbons     connecting them form a five-membered ring B, wherein ring A is

and ring B is

-   wherein each R⁶ in each ring is the same and is H or C₁-C₆ alkyl,     and each R⁷ each ring is the same and is H or C₁-C₆ alkyl; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   each R¹⁰ is the same and is selected from H and C₁-C₆ alkyl; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, provided herein is a compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O; -   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂; -   R² is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy; -   R³ is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy; -   R⁴ is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy     and is the same as R²; -   R⁵ is hydrogen or C₁-C₆ alkyl optionally substituted with hydroxy     and is the same as R³; -   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl; -   or R² and R³ taken together with the carbons connecting them form a     five-membered ring A and R⁴ and R⁵ taken together with the carbons     connecting them form a five-membered ring B, wherein ring A is

and ring B is

wherein each R⁶ in each ring is the same and is H or C₁-C₆ alkyl, and each R⁷ in each ring is the same and is H or C₁-C₆ alkyl;

-   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   each R¹⁰ is the same and is selected from H and C₁-C₆ alkyl; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, a compound of Formula I is a compound of Formula I(A):

or a pharmaceutically acceptable salt thereof, wherein

-   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂; -   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl; -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A, -   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B, -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B, -   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², and     C₃-C₆ cycloalkyl; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   each of R¹¹, R¹² and R¹³ at each occurrence is independently     selected from hydrogen and C₁-C₆ alkyl; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, a compound of Formula I is a compound of Formula I(A):

or a pharmaceutically acceptable salt thereof, wherein

-   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂; -   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl; -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A, -   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B, -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B, -   wherein ring A is

and ring B is

-   wherein -   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², and     C₃-C₆ cycloalkyl; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   each of R¹¹, R¹² and R¹³ at each occurrence is independently     selected from hydrogen and C₁-C₆ alkyl; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.

In some embodiments, the compound of Formula I(A) is a compound of Formula I(A)-i:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I(A) (including I(A)-i), R² and R⁴ are each isopropyl.

In some embodiments, the compound of Formula I(A) is a compound of Formula I(A)-ii:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I(A) (including I(A)-ii), R³ and R⁵ are each isopropyl.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R⁸ is H.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R⁸ is CN.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R⁸ is Cl.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R⁸ is F.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R⁸ is CO₂C₁-C₆ alkyl.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R⁸ is CONH₂.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R¹ is H.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R¹ is CN.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R¹ is Cl.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R¹ is F.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R¹⁴ is H.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R¹⁴ is CN.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R¹⁴ is Cl.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R¹⁴ is F.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R¹⁴ is H.

In some embodiments of the compound of Formula I(A) (including I(A)-i and I(A)-ii), R¹⁰ is CH₃.

In some embodiments of the compound of Formula I(A), ring A is a carbocyclic ring and n1 is 3.

In some embodiments of the compound of Formula I(A), ring A is a carbocyclic ring and n1 is 4.

In some embodiments of the compound of Formula I(A), ring A is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n1 is 3.

In some embodiments of the compound of Formula I(A), ring A is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n1 is 4.

In some embodiments of the compound of Formula I(A), ring B is a carbocyclic ring and n2 is 3.

In some embodiments of the compound of Formula I(A), ring B is a carbocyclic ring and n2 is 4.

In some embodiments of the compound of Formula I(A), ring B is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n2 is 3.

In some embodiments of the compound of Formula I(A), ring B is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n2 is 4.

In some embodiments, the compound of Formula I is a compound of Formula I(B):

wherein

-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂; -   wherein -   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², and     C₃-C₆ cycloalkyl; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   and each of R¹¹, R¹² and R¹³ at each occurrence is independently     selected from hydrogen and C₁-C₆ alkyl.

In some embodiments, the compound of Formula I(B) is a compound of Formula I(B)-i:

In some embodiments, the compound of Formula I(B) is a compound of Formula I(B)-ii:

or a pharmaceutically acceptable salt thereof.

In some embodiments, the compound of Formula I(B) is a compound of Formula I(B)-iii:

or a pharmaceutically acceptable salt thereof.

In some embodiments of the compound of Formula I(B) (including Formula I(B)-i, I(B)ii and I(B)-iii), each R⁶ is hydrogen.

In some embodiments of the compound of Formula I(B) (including Formula I(B)-ii and I(B)-iii), each R⁶ is hydrogen and each R⁷ is hydrogen.

In some embodiments of the compound of Formula I(B) (including Formula I(B)-i, I(B)ii and I(B)-iii), R⁸ is H.

In some embodiments of the compound of Formula I(B) (including Formula I(B)-i, I(B)ii and I(B)-iii), R⁸ is CN.

In some embodiments of the compound of Formula I(B) (including Formula I(B)-i, I(B)ii and I(B)-iii), R⁸ is Cl.

In some embodiments of the compound of Formula I(B) (including Formula I(B)-i, I(B)ii and I(B)-iii), R⁸ is F.

In some embodiments of the compound of Formula I(B) (including Formula I(B)-i, I(B)ii and I(B)-iii), R¹ is H.

In some embodiments of the compound of Formula I(B) (including Formula I(B)-i, I(B)ii and I(B)-iii), R¹ is CN.

In some embodiments of the compound of Formula I(B) (including Formula I(B)-i, I(B)ii and I(B)-iii), R¹ is Cl.

In some embodiments of the compound of Formula I(B) (including Formula I(B)-i, I(B)ii and I(B)-iii), R¹ is F.

In some embodiments of the compound of Formula I(B) (including Formula I(B)-ii, R⁹ is C₁-C₆ alkyl.

In some embodiments of the compound of Formula I(B) (including Formula I(B)-ii, R⁹ is C(R¹⁰)₂OH,

In some embodiments of the compound of Formula I(B) (including Formula I(B)-ii, R⁹ is C(R¹⁰)₂NR¹¹R¹².

In some embodiments of the compound of Formula I(B) (including Formula I(B)-ii, R⁹ is C₃-C₆ cycloalkyl.

In some embodiments of the compound of Formula I(B) (including I(B)-i and I(B)-ii), R¹⁰ is H.

In some embodiments of the compound of Formula I(B) (including I(B)-i and I(B)-iii), R¹⁰ is CH₃.

In some embodiments of the compound of Formula I(B) (including I(B)-i), ring A is a carbocyclic ring and n1 is 3.

In some embodiments of the compound of Formula I(B) (including I(B)-i), ring A is a carbocyclic ring and n1 is 4.

In some embodiments of the compound of Formula I(B) (including I(B)-i), ring A is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n1 is 3.

In some embodiments of the compound of Formula I(B) (including I(B)-i), ring A is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n1 is 4.

In some embodiments of the compound of Formula I(B) (including I(B)-i), ring B is a carbocyclic ring and n2 is 3.

In some embodiments of the compound of Formula I(B) (including I(B)-i), ring B is a carbocyclic ring and n2 is 4.

In some embodiments of the compound of Formula I(B) (including I(B)-i), ring B is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n2 is 3.

In some embodiments of the compound of Formula I(B) (including I(B)-i), ring B is a heterocyclic ring containing 1 or 2 heteroatoms independently selected from O, N, and S and n2 is 4.

In some embodiments, the compound of Formula II is a compound of Formula IIa:

In some embodiments, the compound of Formula II is a compound of Formula IIb:

In some embodiments, the compound of Formula II is a compound of Formula IIc:

In some embodiments, the compound of Formula II is a compound of Formula IId:

In some embodiments, the compound of Formula II is a compound of Formula IIe:

Exemplary embodiments provided herein include the following embodiments 1)-81):

-   -   1) A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O; -   or when X¹ is NH, X¹ and R² taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   or when X¹ is NH, X¹ and R⁴ taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; -   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl; -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A, -   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B, -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B, -   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹²; oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹²; C₃-C₆     cycloalkyl and C₃-C₆ heterocycloalkyl; -   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆     heterocycloalkyl, R⁹ is optionally substituted with one or more     substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,     and CONR¹¹R¹²; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   or two R¹⁰ taken together with the carbon connecting them form a     three-to-eight-membered heterocyclic ring containing 1 or 2     heteroatoms independently selected from O, N, and S, or a     three-membered, six-membered, seven-membered, or eight-membered     carbocyclic ring, wherein the heterocyclic ring or carbocyclic ring     is optionally substituted with one or more substituents each     independently selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹²;     oxo, and ═NR¹³; -   R¹³ is C₁-C₆ alkyl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen, C₁-C₆ alkyl, -   CO₂R¹⁵ and CONR¹⁷R¹⁸; -   R¹⁵ is C₁-C₆ alkyl; -   each of R¹⁷ and R¹⁸ at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl; -   each R¹⁶ is the same or different and is selected from H, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.     -   2) A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O; -   or when X¹ is NH, X¹ and R² taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   or when X¹ is NH, X¹ and R⁴ taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; -   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl; -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A, -   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B, -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B, -   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆     cycloalkyl and C₃-C₆ heterocycloalkyl; -   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆     heterocycloalkyl, R⁹ is optionally substituted with one or more     substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,     and CONR¹¹R¹²; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   R¹³ is C₁-C₆ alkyl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen, C₁-C₆ alkyl, -   CO₂R¹⁵ and CONR¹⁷R¹⁸; -   R¹⁵ is C₁-C₆ alkyl; -   each of R¹⁷ and R¹⁸ at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl; -   each R¹⁶ is the same or different and is selected from H, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.     -   3) A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O; -   or when X¹ is NH, X¹ and R² taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   or when X¹ is NH, X¹ and R⁴ taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; -   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl; -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A, -   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B, -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B, -   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆     cycloalkyl and C₃-C₆ heterocycloalkyl; -   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆     heterocycloalkyl, R⁹ is optionally substituted with one or more     substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,     and CONR¹¹R¹²; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   R¹³ is C₁-C₆ alkyl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen, C₁-C₆ alkyl, -   CO₂R¹⁵ and CONR¹⁷R¹⁸; -   R¹⁵ is C₁-C₆ alkyl; -   each of R¹⁷ and R¹⁸ at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl; each R¹⁶ is the same or different and     is selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and     ═NR¹³; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.

4) A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O; -   or when X¹ is NH, X¹ and R² taken together with the atoms connecting     them form a four-to-seven-membered heterocyclic ring optionally     substituted with one or more R¹⁶; -   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; -   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl; -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A, -   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B, -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B,     wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆     cycloalkyl and C₃-C₆ heterocycloalkyl; -   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆     heterocycloalkyl, R⁹ is optionally substituted with one or more     substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,     and CONR¹¹R¹²; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   R¹³ is C₁-C₆ alkyl; -   each of R¹¹ and R¹² at each occurrence is independently selected     from hydrogen, C₁-C₆ alkyl, CO₂R¹⁵ and CONR¹⁷R¹⁸; -   R¹⁵ is C₁-C₆ alkyl; -   each of R¹⁷ and R¹⁸ at each occurrence is independently selected     from hydrogen and C₁-C₆ alkyl; -   each R¹⁶ is the same or different and is selected from H, C₁-C₆     alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.     -   5) A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O; -   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; -   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl; -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A, -   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B, -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B, -   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆     cycloalkyl and C₃-C₆ heterocycloalkyl; -   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆     heterocycloalkyl, R⁹ is optionally substituted with one or more     substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,     and CONR¹¹R¹²; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   each of R¹¹, R¹² and R¹³ at each occurrence is independently     selected from hydrogen and C₁-C₆ alkyl; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or Cl.     -   6) A compound of Formula I

or a pharmaceutically acceptable salt thereof, wherein:

-   X¹ is NH or O; -   Y is N or CR⁸; -   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl, CO₂C₃-C₈     cycloalkyl, CONR¹¹R¹², C₁-C₆ alkyl, and C₁-C₆ haloalkyl; -   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy; -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A, -   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B, -   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B, -   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², C₃-C₆     cycloalkyl and C₃-C₆ heterocycloalkyl; -   wherein, when R⁹ is C₁-C₆ alkyl, C₃-C₆ cycloalkyl or C₃-C₆     heterocycloalkyl, R⁹ is optionally substituted with one or more     substituents each independently selected from ═NR¹³, COOC₁-C₆ alkyl,     and CONR¹¹R¹²; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   each of R¹¹, R¹² and R¹³ at each occurrence is independently     selected from hydrogen and C₁-C₆ alkyl; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.     -   7) The compound of any one of claims 1 to 4, wherein X¹ is NH.     -   8) The compound of any one of claims 1 to 4, wherein X¹ is O.     -   9) The compound of claim 1, wherein X¹ and R² taken together         with the atoms connecting them form a four-to-seven-membered         heterocyclic ring optionally substituted with one or more R¹⁶.     -   10) The compound of claim 1, wherein X¹ and R⁴ taken together         with the atoms connecting them form a four-to-seven-membered         heterocyclic ring optionally substituted with one or more oxo.     -   11) The compound of claim 1, wherein X¹ and R² taken together         with the atoms connecting them form a four-to-seven-membered         heterocyclic ring optionally substituted with one or more C₁-C₆         alkyl.     -   12) The compound of claim 1, wherein X¹ and R⁴ taken together         with the atoms connecting them form a four-to-seven-membered         heterocyclic ring optionally substituted with one or more         methyl.     -   13) The compound of claim 1, wherein X¹ and R⁴ taken together         with the atoms connecting them form a four-to-seven-membered         heterocyclic ring optionally substituted with one or more C₁-C₆         alkoxy.     -   14) The compound of any one of claims 1 to 13, wherein Y is CR⁸.     -   15) The compound of any one of claims 1 to 13, wherein Y is N.     -   16) The compound of claim 14 or 15, wherein R² is hydrogen.     -   17) The compound of claim 14 or 15, wherein R² is C₁-C₆ alkyl         optionally substituted with hydroxy.     -   18) The compound of claim 14 or 15, wherein R² is isopropyl.     -   19) The compound of claim 14 or 15, wherein R² is methyl.     -   20) The compound of any one of claims 14 to 19, wherein R³ is         hydrogen.     -   21) The compound of any one of claims 14 to 19, wherein R³ is         C₁-C₆ alkyl optionally substituted with hydroxy.     -   22) The compound of any one of claims 14 to 19, wherein R³ is         isopropyl.     -   23) The compound of any one of claims 14 to 19, wherein R³ is         methyl.     -   24) The compound of any one of claims 14 to 23, wherein R⁴ is         hydrogen.     -   25) The compound of any one of claims 14 to 23, wherein R⁴ is         C₁-C₆ alkyl optionally substituted with hydroxy.     -   26) The compound of any one of claims 14 to 23, wherein R⁴ is         isopropyl.     -   27) The compound of any one of claims 14 to 23, wherein R⁴ is         methyl.     -   28) The compound of any one of claims 14 to 27, wherein R⁵ is         hydrogen.     -   29) The compound of any one of claims 14 to 27, wherein R⁵ is         C₁-C₆ alkyl optionally substituted with hydroxy.     -   30) The compound of any one of claims 14 to 27, wherein R⁵ is         isopropyl.     -   31) The compound of any one of claims 14 to 27, wherein R⁵ is         methyl.     -   32) The compound of any one of claims 14 to 15 or 24 to 31,         wherein R² and R³ taken together with the carbons connecting         them form ring A.     -   33) The compound of any one of claim 14 to 24 or 32, wherein R²         and R³ taken together with the carbons connecting them form ring         B.     -   34) The compound of claim 32 or 33, wherein ring A is the same         as ring B.     -   35) The compound of claim 32, 33 or 34, wherein ring A is

-   -   36) The compound of any one of claims 32 to 35, wherein ring B         is

-   -   37) The compound of claim 35 or 36, wherein n1 is 3.     -   38) The compound of claim 35 or 36, wherein n1 is 4.     -   39) The compound of any one of claims 35 to 38, wherein n2 is 3.     -   40) The compound of any one of claims 35 to 38, wherein n2 is 4.     -   41) The compound of any one of claims 35 to 40, wherein R⁶ is H.     -   42) The compound of any one of claims 1 to 14 or 16 to 41,         wherein R⁸ is H.     -   43) The compound of any one of claims 1 to 14 or 16 to 41,         wherein R⁸ is CN.     -   44) The compound of any one of claims 1 to 14 or 16 to 41,         wherein R⁸ is Cl.     -   45) The compound of any one of claims 1 to 14 or 16 to 41,         wherein R⁸ is F.     -   46) The compound of any one of claims 1 to 14 or 16 to 41,         wherein R⁸ is C₁-C₆ alkyl.     -   47) The compound of any one of claims 1 to 14 or 16 to 41,         wherein R⁸ is C₁-C₆ haloalkyl.     -   48) The compound of any one of claims 1 to 14 or 16 to 41,         wherein R⁸ is CF₃.     -   49) The compound of any one of claims 1 to 48, wherein R¹ is H.     -   50) The compound of any one of claims 1 to 48, wherein R¹ is CN.     -   51) The compound of any one of claims 1 to 48, wherein R¹ is Cl.     -   52) The compound of any one of claims 1 to 48, wherein R¹ is F.     -   53) The compound of any one of claims 1 to 52, wherein R¹⁴ is H.     -   54) The compound of any one of claims 1 to 52, wherein R¹⁴ is         CN.     -   55) The compound of any one of claims 1 to 52, wherein R¹⁴ is         Cl.     -   56) The compound of any one of claims 1 to 52, wherein R¹⁴ is F.     -   57) The compound of any one of claims 1 to 56, wherein R⁹ is         C(R¹⁰)₂OH.     -   58) The compound of any one of claims 1 to 56, wherein R⁹ is         C(R¹⁰)₂NR¹¹R¹².     -   59) The compound of any one of claims 1 to 56, wherein R⁹ is         C₁-C₆ alkyl.     -   60) The compound of any one of claims 1 to 56, wherein R⁹ is         C₃-C₆ cycloalkyl.     -   61) The compound of any one of claims 1 to 58, wherein each R¹⁰         is H.     -   62) The compound of any one of claims 1 to 58, wherein each R¹⁰         is C₁-C₆ alkyl.     -   63) The compound of any one of claims 1 to 58, wherein each R¹⁰         is methyl.     -   64) The compound of any one of claims 1 to 58, wherein two R¹⁰         taken together with the carbon connecting them form a         three-to-eight-membered heterocyclic ring containing 1 or 2         heteroatoms independently selected from O, N, and S.     -   65) The compound of any one of claims 1 to 58, wherein two R¹⁰         taken together with the carbon connecting them form a         three-membered, six-membered, seven-membered, or eight-membered         carbocyclic ring.     -   66) The compound of any one of claim 64 or 65, wherein formed by         the two R¹⁰ is optionally substituted with one or more         substituents each independently selected from H, C₁-C₆ alkyl,         C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³.     -   67) The compound of claim 1, wherein each R¹¹ is hydrogen.     -   68) The compound of claim 1, wherein each R¹¹ is C₁-C₆ alkyl.     -   69) The compound of claim 1 or 67 to 68, wherein each R¹² is         hydrogen.     -   70) The compound of claim 1 or 67 to 68, wherein each R¹² is         C₁-C₆ alkyl.     -   71) The compound of any one of claims 1 to 4 or 10 to 13,         wherein each R¹⁶ is hydrogen.     -   72) The compound of any one of claims 1 to 71, wherein if R² and         R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is C₁-C₆ alkyl; R¹⁴ is         H; and R¹ is H, then R⁸ is not F or Cl.     -   73) The compound of any one of claims 1 to 71, wherein if R² and         R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is C₁-C₆ alkyl; and R¹         is H,         -   then R⁸ is not F or Cl.     -   74) A compound of any one of claims 1 to 4, wherein the compound         is a compound of Formula I(A):

-   -   -   or a pharmaceutically acceptable salt thereof, wherein

-   Y is N or CR⁸;

-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂;

-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy;

-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy;

-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy;

-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy;

-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl;

-   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A,

-   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B,

-   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B,

-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², and     C₃-C₆ cycloalkyl; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   each of R¹¹, R¹² and R¹³ at each occurrence is independently     selected from hydrogen and C₁-C₆ alkyl;     -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each         R¹⁰ is C₁-C₆ alkyl; R¹⁴ is H; and R¹ is H, then R⁸ is not F or         Cl.     -   75) A compound of any one of claims 1 to 4, wherein the compound         is a compound of Formula I(A):

-   -   -   or a pharmaceutically acceptable salt thereof, wherein

-   Y is N or CR⁸;

-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂;

-   R² is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy;

-   R³ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy;

-   R⁴ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy;

-   R⁵ is hydrogen, C₁-C₆ alkoxy, halo, C₁-C₆ haloalkyl, or C₁-C₆ alkyl     optionally substituted with hydroxy;

-   provided that at least one of R², R³, R⁴ and R⁵ is not hydrogen, and     that R² and R⁴ are not both hydroxymethyl;

-   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A,

-   or R⁴ and R⁵ taken together with the carbons connecting them form a     four-membered to seven-membered ring B,

-   or R² and R³ taken together with the carbons connecting them form a     four-membered to seven-membered ring A and R⁴ and R⁵ taken together     with the carbons connecting them form a four-membered to     seven-membered ring B,

-   wherein ring A is

and ring B is

wherein

-   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², and     C₃-C₆ cycloalkyl; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   each of R¹¹, R¹² and R¹³ at each occurrence is independently     selected from hydrogen and C₁-C₆ alkyl; -   provided that if R² and R⁴ are each isopropyl; X¹ is NH; each R¹⁰ is     C₁-C₆ alkyl; and R¹ is H, then R⁸ is not F or Cl.     -   76) A compound of any one of claims 1 to 4 or 74 to 75, wherein         the compound is a compound of Formula I(A)-i:

-   -   -   or a pharmaceutically acceptable salt thereof.

    -   77) A compound of any one of claims 1 to 4 or 74 to 76, wherein         the compound is a compound of Formula I(A)-ii:

-   -   -   or a pharmaceutically acceptable salt thereof.

    -   78) A compound of any one of claims 1 to 4, wherein the compound         is a compound of Formula I(B):

wherein

-   R⁸ is selected from H, CN, Cl, F, CO₂C₁-C₆ alkyl and CONH₂; -   wherein -   ring A is a carbocyclic ring or a heterocyclic ring containing 1 or     2 heteroatoms independently selected from O, N, and S; -   n1 is from 2 to 5; -   m1 is from 1 to 10; -   wherein ring B is a carbocyclic ring or a heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   n2 is from 2 to 5; -   m2 is from 1 to 10; -   wherein each R⁶ in each ring is the same or different and is     selected from H, C₁-C₆ alkyl, C₁-C₆ alkoxy, NR¹¹R¹², oxo, and ═NR¹³; -   or two R⁶ taken together with the atom or atoms connecting them form     a 3-to-8-membered carbocyclic or saturated heterocyclic ring     containing 1 or 2 heteroatoms independently selected from O, N, and     S; -   R¹ is selected from H, CN, Cl, or F; -   R¹⁴ is selected from H, CN, Cl, or F; -   R⁹ is selected from C₁-C₆ alkyl, C(R¹⁰)₂OH, C(R¹⁰)₂NR¹¹R¹², and     C₃-C₆ cycloalkyl; -   each R¹⁰ is the same and is H or C₁-C₆ alkyl; -   and each of R¹¹, R¹² and R¹³ at each occurrence is independently     selected from hydrogen and C₁-C₆ alkyl.     -   79) A compound of any one of claim 1 to 4 or 78, wherein the         compound is a compound of Formula I(B)-i:

-   -   -   or a pharmaceutically acceptable salt thereof

    -   80) A compound of any one of claim 1 to 4 or 78, wherein the         compound is a compound of Formula I(B)-ii:

-   -   -   or a pharmaceutically acceptable salt thereof.

    -   81) A compound of any one of claim 1 to 4 or 78, wherein the         compound is a compound of Formula I(B)-iii:

-   -   -   or a pharmaceutically acceptable salt thereof.

In some embodiments, provided herein is a compound selected from the group consisting of compounds in Table 1 below, and NLRP1 antagonist activity is shown for compounds for which data is available. <1 μM=“++++”, ≥1 and <5 μM=“++++”, ≥5 and <15 μM=“++”, ≥15 and <35 μM=“+”.

TABLE 1 hNLRP3 (THP- 1, IL-1β) Average IC₅₀ Compound Structure (μM) 101

+++ 102

+++ 103

+++ 104

105

+++ 106

107

+++ 108

+++ 109

+++ 110

++++ 111

++++ 112

++++ 113

++++ 114

++++ 115

++++ 116

++++ 117

++++ 118

119

120

++++ 121

122

123

++++ 124

+++ 125

+++ 126

++++ 127

++++ 128

131

++++ 132

135

136

and pharmaceutically acceptable salts thereof.

In some embodiments, provided herein is a compound selected from the group consisting of compounds in Table 2 below, and NLRP1 antagonist activity is shown for compounds for which data is available. <1 μM=“++++”; ≥1 and <5 μM=“+++”; ≥5 and <15 μM=“++”; ≥15 and <35 μM=“+”.

TABLE 2 hNLRP3 (THP- 1, IL-1β) Average IC₅₀ Compound Structure (μM) 137

++++ 138

++++ 141

++++ 142

++++ 143

++++ 144

++++ 145

++++ 146

++++ 147

++++ 148

+++ 149

+++ 150

+++ 151

+++ 153

+++ 154

+++ 155

+++ 157

+++ 158

++ 159

++ 160

++++ 161

++++ 162

++++ 163

++++ 164

++++ 165

++++ 166

++++ 167

++++ 168

+++ 169

+++ 170

+++ 171

+++

and pharmaceutically acceptable salts thereof.

Pharmaceutical Compositions and Administration

General

In some embodiments, a chemical entity (e.g., a compound that modulates (e.g., antagonizes) NLRP1 or NLRP3 or both NLRP1 and NLRP3, or a pharmaceutically acceptable salt and/or hydrate, and/or cocrystal, and/or drug combination thereof) is administered as a pharmaceutical composition that includes the chemical entity and one or more pharmaceutically acceptable excipients, and optionally one or more additional therapeutic agents as described herein.

In some embodiments, the chemical entities can be administered in combination with one or more conventional pharmaceutical excipients. Pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-emulsifying drug delivery systems (SEDDS) such as d-α-tocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms such as Tweens, poloxamers or other similar polymeric delivery matrices, serum proteins, such as human serum albumin, buffer substances such as phosphates, tris, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium-chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, and wool fat. Cyclodextrins such as α-, β, and γ-cyclodextrin, or chemically modified derivatives such as hydroxyalkylcyclodextrins, including 2- and 3-hydroxypropyl-β-cyclodextrins, or other solubilized derivatives can also be used to enhance delivery of compounds described herein. Dosage forms or compositions containing a chemical entity as described herein in the range of 0.005% to 100% with the balance made up from non-toxic excipient may be prepared. The contemplated compositions may contain 0.001%-100% of a chemical entity provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%. Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington: The Science and Practice of Pharmacy, 22^(nd) Edition (Pharmaceutical Press, London, UK. 2012).

Routes of Administration and Composition Components

In some embodiments, the chemical entities described herein or a pharmaceutical composition thereof can be administered to subject in need thereof by any accepted route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intra-arterial, intrabronchial, intrabursal, intracerebral, intraci sternal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal. In certain embodiments, a preferred route of administration is parenteral (e.g., intratumoral).

Compositions can be formulated for parenteral administration, e.g., formulated for injection via the intravenous, intramuscular, sub-cutaneous, or even intraperitoneal routes. Typically, such compositions can be prepared as injectables, either as liquid solutions or suspensions; solid forms suitable for use to prepare solutions or suspensions upon the addition of a liquid prior to injection can also be prepared; and the preparations can also be emulsified. The preparation of such formulations will be known to those of skill in the art in light of the present disclosure.

The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil, or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases the form must be sterile and must be fluid to the extent that it may be easily injected. It also should be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.

The carrier also can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion, and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum-drying and freeze-drying techniques, which yield a powder of the active ingredient, plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Intratumoral injections are discussed, e.g., in Lammers, et al., “Effect of Intratumoral Injection on the Biodistribution and the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems” Neoplasia. 2006, 10, 788-795.

Pharmacologically acceptable excipients usable in the rectal composition as a gel, cream, enema, or rectal suppository, include, without limitation, any one or more of cocoa butter glycerides, synthetic polymers such as polyvinylpyrrolidone, PEG (like PEG ointments), glycerine, glycerinated gelatin, hydrogenated vegetable oils, poloxamers, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol Vaseline, anhydrous lanolin, shark liver oil, sodium saccharinate, menthol, sweet almond oil, sorbitol, sodium benzoate, anoxid SBN, vanilla essential oil, aerosol, parabens in phenoxyethanol, sodium methyl p-oxybenzoate, sodium propyl p-oxybenzoate, diethylamine, carbomers, carbopol, methyloxybenzoate, macrogol cetostearyl ether, cocoyl caprylocaprate, isopropyl alcohol, propylene glycol, liquid paraffin, xanthan gum, carboxy-metabisulfite, sodium edetate, sodium benzoate, potassium metabisulfite, grapefruit seed extract, methyl sulfonyl methane (MSM), lactic acid, glycine, vitamins, such as vitamin A and E and potassium acetate.

In certain embodiments, suppositories can be prepared by mixing the chemical entities described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound. In other embodiments, compositions for rectal administration are in the form of an enema.

In other embodiments, the compounds described herein or a pharmaceutical composition thereof are suitable for local delivery to the digestive or GI tract by way of oral administration (e.g., solid or liquid dosage forms).

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the chemical entity is mixed with one or more pharmaceutically acceptable excipients, such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

In one embodiment, the compositions will take the form of a unit dosage form such as a pill or tablet and thus the composition may contain, along with a chemical entity provided herein, a diluent such as lactose, sucrose, dicalcium phosphate, or the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives or the like. In another solid dosage form, a powder, marume, solution or suspension (e.g., in propylene carbonate, vegetable oils, PEG's, poloxamer 124 or triglycerides) is encapsulated in a capsule (gelatin or cellulose base capsule). Unit dosage forms in which one or more chemical entities provided herein or additional active agents are physically separated are also contemplated; e.g., capsules with granules (or tablets in a capsule) of each drug; two-layer tablets; two-compartment gel caps, etc. Enteric coated or delayed release oral dosage forms are also contemplated.

Other physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid.

In certain embodiments the excipients are sterile and generally free of undesirable matter. These compositions can be sterilized by conventional, well-known sterilization techniques. For various oral dosage form excipients such as tablets and capsules sterility is not required. The USP/NF standard is usually sufficient.

In certain embodiments, solid oral dosage forms can further include one or more components that chemically and/or structurally predispose the composition for delivery of the chemical entity to the stomach or the lower GI; e.g., the ascending colon and/or transverse colon and/or distal colon and/or small bowel. Exemplary formulation techniques are described in, e.g., Filipski, K. J., et al., Current Topics in Medicinal Chemistry, 2013, 13, 776-802, which is incorporated herein by reference in its entirety.

Examples include upper-GI targeting techniques, e.g., Accordion Pill (Intec Pharma), floating capsules, and materials capable of adhering to mucosal walls.

Other examples include lower-GI targeting techniques. For targeting various regions in the intestinal tract, several enteric/pH-responsive coatings and excipients are available. These materials are typically polymers that are designed to dissolve or erode at specific pH ranges, selected based upon the GI region of desired drug release. These materials also function to protect acid labile drugs from gastric fluid or limit exposure in cases where the active ingredient may be irritating to the upper GI (e.g., hydroxypropyl methylcellulose phthalate series, Coateric (polyvinyl acetate phthalate), cellulose acetate phthalate, hydroxypropyl methylcellulose acetate succinate, Eudragit series (methacrylic acid-methyl methacrylate copolymers), and Marcoat). Other techniques include dosage forms that respond to local flora in the GI tract, Pressure-controlled colon delivery capsule, and Pulsincap.

Ocular compositions can include, without limitation, one or more of any of the following: viscogens (e.g., Carboxymethylcellulose, Glycerin, Polyvinylpyrrolidone, Polyethylene glycol); Stabilizers (e.g., Pluronic (triblock copolymers), Cyclodextrins); Preservatives (e.g., Benzalkonium chloride, ETDA, SofZia (boric acid, propylene glycol, sorbitol, and zinc chloride; Alcon Laboratories, Inc.), Purite (stabilized oxychloro complex; Allergan, Inc.)).

Topical compositions can include ointments and creams. Ointments are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil. Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and non-sensitizing.

In any of the foregoing embodiments, pharmaceutical compositions described herein can include one or more one or more of the following: lipids, interbilayer crosslinked multilamellar vesicles, biodegradeable poly(D,L-lactic-co-glycolic acid) [PLGA]-based or poly anhydride-based nanoparticles or microparticles, and nanoporous particle-supported lipid bilayers.

Dosages

The dosages may be varied depending on the requirement of the patient, the severity of the condition being treating and the particular compound being employed. Determination of the proper dosage for a particular situation can be determined by one skilled in the medical arts. The total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.

In some embodiments, the compounds described herein are administered at a dosage of from about 0.001 mg/Kg to about 500 mg/Kg (e.g., from about 0.001 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 200 mg/Kg; from about 0.01 mg/Kg to about 150 mg/Kg; from about 0.01 mg/Kg to about 100 mg/Kg; from about 0.01 mg/Kg to about 50 mg/Kg; from about 0.01 mg/Kg to about 10 mg/Kg; from about 0.01 mg/Kg to about 5 mg/Kg; from about 0.01 mg/Kg to about 1 mg/Kg; from about 0.01 mg/Kg to about 0.5 mg/Kg; from about 0.01 mg/Kg to about 0.1 mg/Kg; from about 0.1 mg/Kg to about 200 mg/Kg; from about 0.1 mg/Kg to about 150 mg/Kg; from about 0.1 mg/Kg to about 100 mg/Kg; from about 0.1 mg/Kg to about 50 mg/Kg;

from about 0.1 mg/Kg to about 10 mg/Kg; from about 0.1 mg/Kg to about 5 mg/Kg; from about 0.1 mg/Kg to about 1 mg/Kg; from about 0.1 mg/Kg to about 0.5 mg/Kg).

Regimens

The foregoing dosages can be administered on a daily basis (e.g., as a single dose or as two or more divided doses) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weeks, once every two weeks, once a month).

In some embodiments, the period of administration of a compound described herein is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In an embodiment, a therapeutic compound is administered to an individual for a period of time followed by a separate period of time. In another embodiment, a therapeutic compound is administered for a first period and a second period following the first period, with administration stopped during the second period, followed by a third period where administration of the therapeutic compound is started and then a fourth period following the third period where administration is stopped. In an aspect of this embodiment, the period of administration of a therapeutic compound followed by a period where administration is stopped is repeated for a determined or undetermined period of time. In a further embodiment, a period of administration is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more. In a further embodiment, a period of during which administration is stopped is for 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or more.

Methods of Treatment

In some embodiments, methods for treating a subject having condition, disease or disorder in which a decrease or increase in NLRP1 or NLRP3 or both NLRP1 and NLRP3 activity (e.g., an increase, e.g., NLRP1/3 signaling) contributes to the pathology and/or symptoms and/or progression of the condition, disease or disorder are provided, comprising administering to a subject an effective amount of a chemical entity described herein (e.g., a compound described generically or specifically herein or a pharmaceutically acceptable salt thereof or compositions containing the same).

Indications

In some embodiments, the condition, disease or disorder is selected from: inappropriate host responses to infectious diseases where active infection exists at any body site, such as septic shock, disseminated intravascular coagulation, and/or adult respiratory distress syndrome; acute or chronic inflammation due to antigen, antibody and/or complement deposition; inflammatory conditions including arthritis, cholangitis, colitis, encephalitis, endocarditis, glomerulonephritis, hepatitis, myocarditis, pancreatitis, pericarditis, reperfusion injury and vasculitis, immune-based diseases such as acute and delayed hypersensitivity, graft rejection, and graft-versus-host disease; auto-immune diseases including Type 1 diabetes mellitus and multiple sclerosis. For example, the condition, disease or disorder may be an inflammatory disorder such as rheumatoid arthritis, osteoarthritis, septic shock, COPD and periodontal disease.

In some embodiments, the condition, disease or disorder is an autoimmune diseases. Non limiting examples include rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, inflammatory bowel diseases (IBDs) comprising Crohn disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions with polygenic susceptibility. In certain embodiments, the condition is an inflammatory bowel disease. In certain embodiments, the condition is Crohn's disease, autoimmune colitis, iatrogenic autoimmune colitis, ulcerative colitis, colitis induced by one or more chemotherapeutic agents, colitis induced by treatment with adoptive cell therapy, colitis associated by one or more alloimmune diseases (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), radiation enteritis, collagenous colitis, lymphocytic colitis, microscopic colitis, and radiation enteritis. In certain of these embodiments, the condition is alloimmune disease (such as graft-vs-host disease, e.g., acute graft vs. host disease and chronic graft vs. host disease), celiac disease, irritable bowel syndrome, rheumatoid arthritis, lupus, scleroderma, psoriasis, cutaneous T-cell lymphoma, uveitis, and mucositis (e.g., oral mucositis, esophageal mucositis or intestinal mucositis).

In some embodiments, the condition, disease or disorder is selected from metabolic disorders such as type 2 diabetes, atherosclerosis, obesity and gout, as well as diseases of the central nervous system, such as Alzheimer's disease and multiple sclerosis and Amyotrophic Lateral Sclerosis and Parkinson disease, lung disease, such as asthma and COPD and pulmonary idiopathic fibrosis, liver disease, such as NASH syndrome, viral hepatitis and cirrhosis, pancreatic disease, such as acute and chronic pancreatitis, kidney disease, such as acute and chronic kidney injury, intestinal disease such as Crohn's disease and Ulcerative Colitis, skin disease such as psoriasis, musculoskeletal disease such as scleroderma, vessel disorders, such as giant cell arteritis, disorders of the bones, such as osteoarthritis, osteoporosis and osteopetrosis disorders, eye disease, such as glaucoma and macular degeneration, diseases caused by viral infection such as HIV and AIDS, autoimmune diseases such as rheumatoid arthritis, systemic Lupus erythematosus, autoimmune thyroiditis; Addison's disease, and pernicious anemia, cancer and aging.

In some embodiments, the condition, disease or disorder is a cardiovascular indication. In some embodiments, the condition, disease or disorder is myocardial infraction. In some embodiments, the condition, disease or disorder is stroke.

In some embodiments, the condition, disease or disorder is obesity.

In some embodiments, the condition, disease or disorder is Type 2 Diabetes.

In some embodiments, the condition, disease or disorder is NASH.

In some embodiments, the condition, disease or disorder is Alzheimer's disease.

In some embodiments, the condition, disease or disorder is gout.

In some embodiments, the condition, disease or disorder is SLE.

In some embodiments, the condition, disease or disorder is rheumatoid arthritis.

In some embodiments, the condition, disease or disorder is IBD.

In some embodiments, the condition, disease or disorder is multiple sclerosis.

In some embodiments, the condition, disease or disorder is COPD.

In some embodiments, the condition, disease or disorder is asthma.

In some embodiments, the condition, disease or disorder is scleroderma.

In some embodiments, the condition, disease or disorder is pulmonary fibrosis.

In some embodiments, the condition, disease or disorder is age related macular degeneration (AMD).

In some embodiments, the condition, disease or disorder is cystic fibrosis.

In some embodiments, the condition, disease or disorder is Muckle Wells syndrome.

In some embodiments, the condition, disease or disorder is familial cold autoinflammatory syndrome (FCAS).

In some embodiments, the condition, disease or disorder is chronic neurologic cutaneous and articular syndrome.

Combination Therapy

This disclosure contemplates both monotherapy regimens as well as combination therapy regimens.

In some embodiments, the methods described herein can further include administering one or more additional therapies (e.g., one or more additional therapeutic agents and/or one or more therapeutic regimens) in combination with administration of the compounds described herein.

In certain embodiments, the second therapeutic agent or regimen is administered to the subject prior to contacting with or administering the chemical entity (e.g., about one hour prior, or about 6 hours prior, or about 12 hours prior, or about 24 hours prior, or about 48 hours prior, or about 1 week prior, or about 1 month prior).

In other embodiments, the second therapeutic agent or regimen is administered to the subject at about the same time as contacting with or administering the chemical entity. By way of example, the second therapeutic agent or regimen and the chemical entity are provided to the subject simultaneously in the same dosage form. As another example, the second therapeutic agent or regimen and the chemical entity are provided to the subject concurrently in separate dosage forms.

In still other embodiments, the second therapeutic agent or regimen is administered to the subject after contacting with or administering the chemical entity (e.g., about one hour after, or about 6 hours after, or about 12 hours after, or about 24 hours after, or about 48 hours after, or about 1 week after, or about 1 month after).

Patient Selection

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 polymorphism.

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 where polymorphism is a gain of function

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related to NLRP3 polymorphism found in CAPS syndromes.

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related NLRP3 polymorphism where the polymorphism is VAR_014104 (R262W)

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP3 activity, such as an indication related NLRP3 polymorphism where the polymorphism is a natural variant reported in http://www.uniprot.org/uniprot/Q96P20

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP1 activity, such as an indication related NLRP1 polymorphism.

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP1 activity, such as an indication related to NLRP1 where polymorphism is a gain of function

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP1 activity, such as an indication related NLRP1 polymorphism found in vitiligo Vitiligo-Associated Autoimmune Disease.

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP1 activity, such as an indication related where NLRP1 polymorphism is VAR_033239 (L155H)

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP1 activity, such as an indication related where NLRP1 polymorphism is a natural variant reported in http://www.uniprot.org/uniprot/Q9C000

In some embodiments, the methods described herein further include the step of identifying a subject (e.g., a patient) in need of treatment for an indication related to NLRP1/3 activity, such as an indication related to point mutation of NLRP1/3 signaling.

Compound Preparation and Biological Assays

As can be appreciated by the skilled artisan, methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing the compounds described herein are known in the art and include, for example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and R G M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. Suitable methods for the preparation of the compounds herein are also disclosed in patent publications EP 1214087, WO 2001/019390, and WO 98/32733, each of which is incorporated by reference in its entirety.

Scheme 1 shows an example of a method of preparation of compounds disclosed herein:

-   The following abbreviations have the indicated meanings: -   ACN=acetonitrile -   AcOH=acetic acid -   BINAP=(±)-2,2′-(diphenylphosphino)-1,1′-binaphthyl -   BTC=trichloromethyl chloroformate -   DBU=1,8-diazabicycloundec-7-ene -   DCM=dichloromethane -   DMEDA=N,N′-dimethylethylenediamine -   DMF=N,N-dimethylformamide -   DMSO=dimethyl sulfoxide -   Et=ethyl -   EtOH=ethanol -   LC-MS=liquid chromatography-mass spectrometry -   Me=methyl -   MeOH=methanol -   NBS=N-bromosuccinimide -   NCS=N-chlorosuccinimide -   NMR=nuclear magnetic resonance -   Pd₂(dba)₃=tris(dibenzylideneacetone)dipalladium -   Pd(dppf)Cl₂=dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium -   Pd(PPh₃)₄=tetrakis(triphenylphosphine)Palladium(0) -   Ph=phenyl -   HPLC=high performance liquid chromatography -   Py=pyridine -   RT=room temperature -   t-Bu=tert-butyl -   TEA=triethylamine -   THF=tetrahydrofuran -   TLC=thin layer chromatography

Materials and Methods

The progress of reactions was often monitored by TLC or LC-MS. The identity of the products was often confirmed by LC-MS. The LC-MS was recorded using one of the following methods.

Method A: Shim-pack XR-ODS, C18, 3×50 mm, 2.5 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu/scan range, 190-400 nm UV range, 5-100% (1.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA) and water (0.05% TFA), 2 minute total run time.

Method B: Kinetex EVO, C18, 3×50 mm, 2.2 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 10-95% (1.1 min), 95% (0.6 min) gradient with ACN and water (0.5% N₄HCO₃), 2 minute total run time.

Method C: Shim-pack XR-ODS, C18, 3×50 mm, 2.5 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 5-100% (2.1 min), 100% (0.6 min) gradient with ACN (0.05% TFA) and water (0.05% TFA), 3 minute total run time.

Method D: Kinetex EVO, C18, 3×50 mm, 2.2 um column, 1.0 uL injection, 1.5 mL/min flow rate, 90-900 amu scan range, 190-400 nm UV range, 10-95% (2.1 min), 95% (0.6 min) gradient with ACN and water (0.5% NH₄HCO₃), 3 minute total run time.

The final targets were purified by Prep-HPLC. The Prep-HPLC was carried out using the following method.

Method E: Pre-HPLC: Column, XBridge Shield RP18 OBD (19×250 mm, 10 um); mobile phase, Water (10 mmol/L NH₄HCO₃) and ACN, UV detection 254/210 nm.

NMR was recorded on BRUKER NMR 300.03 Mz, DUL-C-H, ULTRASHIELD™ 300, AVANCE II 300 B-ACS™ 120 or BRUKER NMR 400.13 Mz, BBFO, ULTRASHIELD™ 400, AVANCE III 400, B-ACS™ 120.

PREPARATIVE EXAMPLES Preparative Example 1 Compound 131

1. Synthesis of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene

Into a 50-mL round-bottom flask, was placed a solution of 1,2,3,5,6,7-hexahydro-s-indacen-4-amine (100 mg, 0.58 mmol, 1.00 equiv) in tetrahydrofuran (10 mL). To the solution were added TEA (29 mg, 0.29 mmol, 0.50 equiv) and ditrichloromethyl carbonate (51.5 mg, 0.17 mmol, 0.30 equiv). The resulting solution was stirred for 1 h at 60° C. The resulting mixture was concentrated under vacuum. This resulted in 110 mg (crude) of 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene as a white solid.

2. Synthesis of 1-[[2-fluoro-5-(2-hydroxypropan-2-yl)benzene]sulfonyl]-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea (Compound 131)

Into a 50-mL 3-necked round-bottom flask, was placed a solution of 2-fluoro-5-(2-hydroxypropan-2-yl)benzene-1-sulfonamide (130 mg, 0.56 mmol, 1.00 equiv) in tetrahydrofuran (10 mL). To the solution were added DBU (127.21 mg, 0.84 mmol, 1.50 equiv) and 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (110 mg, 0.55 mmol, 0.99 equiv). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (HPLC-10): Column, X Bridge Shield RP18 OBD Column, 19*250 mm, 10 um; mobile phase, Water (10 mmol/L NH₄HCO₃) and ACN (30% ACN up to 51% in 6 min); Detector, UV 254/220 nm. This resulted in 46 mg (19%) of 1-[[2-fluoro-5-(2-hydroxypropan-2-yl)benzene]sulfonyl]-3-(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)urea as a white solid.

LC-MS: (ES, m/z): [M+H]⁺=433.2.

H-NMR: (DMSO-d₆, 400 MHz, ppm): δ 7.97-7.96 (m, 2H), 7.69 (brs, 1H), 7.34-7.29 (m, 1H), 6.89 (s, 1H), 5.28 (s, 1H), 2.76 (t, J=7.2 Hz, 4H), 2.57-2.52 (m, 4H), 1.93-1.89 (m, 4H), 1.41 (s, 6H).

Schemes of final targets: Schemes 2-5 illustrate several conditions used for coupling of amine 1 and sulfonamide 2 to afford sulfonyl urea 3

Schemes of Sulfonamides Intermediates: Schemes 6-12 illustrate the preparation of sulfonamide intermediates.

3-Chloro-5-(2-hydroxypropan-2-yl)benzenesulfonamide Step 1: 3-Chloro-5-(2-hydroxypropan-2-yl)benzenesulfonamide

Into a 100-mL 3-necked round-bottom flask purged with and maintained under nitrogen, was placed a solution of methyl 3-chloro-5-sulfamoylbenzoate (579 mg, 2.32 mmol) in THF (20 mL). This was followed by the addition of MeMgBr/THF (3 M, 3.5 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 12 h at RT and then was quenched by the addition of 20 mL of NH₄Cl (sat.). The solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:3 to 1:1). This resulted in 415 mg (72%) of the title compound as a light yellow solid. MS-ESI: 248.0, 250.0 (M−1).

3-(2-Hydroxypropan-2-yl)benzenesulfonamide Step 1: Methyl 3-sulfamoylbenzoate

Into a 100-mL round-bottom flask, was placed a solution of methyl 3-(chlorosulfonyl)benzoate (2 g, 8.5 mmol) in DCM (35 mL). To the above was added a saturated solution of ammonia in DCM (15 mL). The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:3 to 1:1). This resulted in 1.753 g (93%) of the title compound as a white solid. MS-ESI: 214.0 (M−1).

Step 2: 3-(2-Hydroxypropan-2-yl)benzenesulfonamide

Into a 250-mL 3-necked round-bottom flask purged with and maintained under nitrogen, was placed a solution of methyl 3-sulfamoylbenzoate (1.753 g, 8.14 mmol) in THF (70 mL). This was followed by the addition of MeMgBr/THF (3 M, 12.2 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 12 h at RT and then was quenched by the addition of 30 mL of NH₄Cl (sat.). The resulting solution was extracted with 5×30 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:3 to 1:1). This resulted in 1.642 g (94%) of the title compound as a white solid. MS-ESI: 214.1 (M−1).

TABLE 3 The Intermediate in the following Table was prepared using the similar procedures for converting compound 2 to Intermediate 2 shown in Scheme 7. Intermediate # Structure IUPAC Name Mass Spec [M − H]⁻ Intermediate 19

4-(2-hydroxypropan-2-yl) benzenesulfonamide 214.1

3-Cyano-5-(2-hydroxypropan-2-yl)benzenesulfonamide

Steps 1-2 used similar procedures for converting compound 2 to Intermediate 2 shown in Scheme 6 to afford compound 6. MS-ESI: 292.0 (M−1).

Step 3: 3-Cyano-5-(2-hydroxypropan-2-yl)benzenesulfonamide

Into a 50-mL round-bottom flask purged with and maintained under nitrogen, was placed 3-bromo-5-(2-hydroxypropan-2-yl)benzenesulfonamide (343 mg, 1.17 mmol), DMF (8 mL), CuCN (157 mg, 1.75 mmol), t-BuOK (13 mg, 0.12 mmol), Pd(dppf)Cl₂ (171 mg, 0.23 mmol), and Pd(PPh₃)₄ (138 mg, 0.12 mmol). The resulting solution was stirred for 12 h at 120° C. and then was quenched by the addition of 10 mL of NH₄Cl (sat.). The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 159 mg (57%) of the title compound as a white solid. MS-ESI: 239.1 (M−1).

2-Fluoro-5-(2-hydroxypropan-2-yl)benzenesulfonamide Step 1: Methyl 3-(chlorosulfonyl)-4-fluorobenzoate

Into a 100-mL round-bottom flask, was placed methyl 3-amino-4-fluorobenzoate (1 g, 5.91 mmol), HCl (6 M, 10 mL). This was followed by the addition of a solution of NaNO₂ (630 mg, 9.13 mmol) in water (2 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 20 min at 0° C. The above mixture was added to a saturated solution of SO₂ in AcOH (20 mL) and CuCl₂ (800 mg, 5.95 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 1 h at RT. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. This resulted in 1.5 g (crude) of the title compound as a yellow oil. The crude product was used in the next step.

Steps 2-3 used similar procedures for converting compound 2 to Intermediate 2 shown in Scheme 6 to afford Intermediate 4. MS-ESI: 232.1 (M−1).

TABLE 4 The Intermediates in the following Table were prepared using the similar procedures for converting compound 7 to Intermediate 4 shown in Scheme 9. Intermediate # Structure IUPAC Name Mass Spec [M − H]⁻ Intermediate 5

3-fluoro-5-(2- hydroxypropan-2- yl)benzenesulfonamide 232.1 Intermediate 6

3,5-bis(2-hydroxypropan- 2-yl) benzenesulfonamide 272.1

3-(2-Hydroxypropan-2-yl)-5-(pyridin-4-yl)benzenesulfonamide Step 1: Ethyl 3-nitro-5-(pyridin-4-yl)benzoate

Into a 500-mL round-bottom flask purged with and maintained under nitrogen, was placed ethyl 3-bromo-5-nitrobenzoate (5.5 g, 20.1 mmol), dioxane (250 mL), water (50 mL), (pyridin-4-yl)boronic acid (3.0 g, 24.4 mmol), Cs₂CO₃ (12.7 g, 38.98 mmol), and Pd(dppf)Cl₂ (600 mg, 0.82 mmol). The resulting solution was stirred for 12 h at 100° C. and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:1 to 3:1). This resulted in 4.2 g (77%) of the title compound as a white solid. MS-ESI: 273.1 (M+1).

Step 2: Ethyl 3-amino-5-(pyridin-4-yl)benzoate

Into a 250-mL round-bottom flask, was placed ethyl 3-nitro-5-(pyridin-4-yl)benzoate (4.2 g, 15.4 mmol) and MeOH (150 mL). Then Pd/C (10% wt, 500 mg) was added. The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 2 days at RT under an atmosphere of hydrogen. The solids were then filtered out. The resulting solution was concentrated under vacuum, resulting in 3.7 g (99%) of the title compound as a white solid. MS-ESI: 243.1 (M+1).

Steps 3-5 used the similar procedures for converting compound 7 to Intermediate 4 shown in Scheme 9 to afford Intermediate 7. MS-ESI: 293.1 (M+1), 291.1 (M−1).

TABLE 5 The Intermediate in the following Table was prepared using the similar procedures for converting compound 10 to Intermediate 7 shown in Scheme 10. Intermediate # Structure IUPAC Name Mass Spec [M − H]⁻ Intermediate 8

5-(2-hydroxypropan-2- yl)biphenyl-3- sulfonamide 290.1

3-(2-Hydroxypropan-2-yl)-5-morpholinobenzenesulfonamide Step 1: Ethyl 3-bromo-5-nitrobenzoate

Into a 500-mL round-bottom flask, was placed 3-bromo-5-nitrobenzoic acid (25 g, 101.6 mmol), EtOH (200 mL). This was followed by the addition of SOCl₂ (15 mL) dropwise with stirring at 0° C. The resulting solution was stirred for 4 h at 80° C. and then was quenched by the addition of 50 mL water. The resulting solution was extracted with 3×50 mL of DCM and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:20 to 1:10). This resulted in 27.5 g (99%) of the title compound as a white solid.

Step 2: Ethyl 3-(morpholin-4-yl)-5-nitrobenzoate

Into a 500-mL round-bottom flask purged with and maintained under nitrogen, was placed ethyl 3-bromo-5-nitrobenzoate (10 g, 36.5 mmol), toluene (250 mL), morpholine (4.6 g, 52.8 mmol), t-BuONa (5 g, 52.0 mmol), Pd₂(dba)₃CHCl₃ (1.9 g, 1.93 mmol), and BINAP (1.2 g, 1.93 mmol). The resulting solution was stirred for 18 h at 60° C. and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:30 to 1:10). This resulted in 2.8 g (27%) of the title compound as a yellow solid. MS-ESI: 281.1 (M+1).

Step 3: Ethyl 3-amino-5-(morpholin-4-yl)benzoate

Into a 250-mL round-bottom flask, was placed ethyl 3-(morpholin-4-yl)-5-nitrobenzoate (3.0 g, 10.7 mmol) and MeOH (100 mL). Then Pd/C (10% wt, 300 mg) was added. The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 2.6 g (97%) of the title compound as a yellow solid. MS-ESI: 251.1 (M+1).

Steps 4-6 used the similar procedures for converting compound 7 to Intermediate 4 shown in Scheme 9 to afford Intermediate 9. MS-ESI: 299.1 (M−1).

3-(Hydroxymethyl)-4-(2-hydroxypropan-2-yl)benzenesulfonamide Step 1: 1-Oxo-1,3-dihydroisobenzofuran-5-sulfonyl chloride

Into a 100-mL round-bottom flask, was placed 5-aminoisobenzofuran-1(3H)-one (1 g, 6.70 mmol), HCl (6 M, 10 mL). This was followed by the addition of a solution of NaNO₂ (603 mg, 8.74 mmol) in water (5 mL) dropwise with stirring at 0° C. The above mixture was added to a saturated solution of SO₂ in AcOH (20 mL) dropwise with stirring at 0° C. Then to the above was added CuCl₂ (890 mg, 6.62 mmol). The resulting solution was stirred for 1 h at RT and then was quenched by the addition of 30 mL of water. The resulting solution was extracted with 3×30 mL of DCM and the organic layers combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. This resulted in 1.1 g (crude, 71%) of the title compound as brown oil. The crude product was used in the next step.

Step 2: 1-Oxo-1,3-dihydroisobenzofuran-5-sulfonamide

Into a 100-mL round-bottom flask, was placed 1-oxo-1,3-dihydroisobenzofuran-5-sulfonyl chloride (1.1 g, 4.73 mmol), DCM (20 mL). To the above was added a saturated solution of ammonia in DCM (20 mL). The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:3 to 1:1). This resulted in 480 mg (48%) of the title compound as a yellow solid. MS-ESI: 212.0 (M−1).

Step 3: 3-(Hydroxymethyl)-4-(2-hydroxypropan-2-yl)benzenesulfonamide

Into a 100-mL 3-necked round-bottom flask purged with and maintained under nitrogen, was placed a solution of 1-oxo-1,3-dihydroisobenzofuran-5-sulfonamide (310 mg, 1.45 mmol) in THF (10 mL). This was followed by the addition MeMgBr/THF (3 M, 4.85 mL) dropwise with stirring at 0° C. The resulting solution was stirred overnight at RT and then was quenched by the addition of 10 mL of NH₄Cl (sat.). The resulting solution was extracted with 5×10 mL of ethyl acetate and the organic layers combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. The crude product was purified by Prep-HPLC using method E eluted with a gradient of 5∞20% ACN. This resulted in 200 mg (56%) of the title compound as a white solid. MS-ESI: 244.1 (M−1).

TABLE 6 The Intermediate in the following Table was prepared using the similar procedures for converting compound 32 to Intermediate 20 shown in Scheme 20. Intermediate # Structure IUPAC Name Mass Spec [M + H]⁺ Intermediate 21

6-(2-hydroxypropan-2-yl) pyridine-3-sulfonamide 217.1

TABLE 7 The Intermediate in the following Table was prepared using the similar procedures for converting compound 32 to compound 34 shown in Scheme 20. Mass Spec Intermediate # Structure IUPAC Name [M − H]⁻ Intermediate 22

methyl 4-fluoro-3-sulfamoylbenzoate 232.0

Schemes for amine Intermediates: Schemes 13-21 illustrate the amine intermediates preparation.

4-Fluoro-2,6-diisopropylbenzenamine Step 1: 4-Fluoro-2,6-di(prop-1-en-2-yl)benzenamine

Into a 500-mL round-bottom flask purged with and maintained under nitrogen, was placed 2,6-dibromo-4-fluorobenzenamine (15 g, 55.8 mmol), dioxane (150 mL), water (15 mL), Cs₂CO₃ (55 g, 169 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (25 g, 149 mmol), and Pd(dppf)Cl₂ (4 g, 5.47 mmol). The resulting solution was stirred for 15 h at 100° C. and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10 to 1:8). This resulted in 9.2 g (86%) of the title compound as brown oil. MS-ESI: 192.1 (M+1).

Step 2: 4-Fluoro-2,6-diisopropylbenzenamine

Into a 500-mL round-bottom flask, was placed 4-fluoro-2,6-di(prop-1-en-2-yl)benzenamine (9.2 g, 48.1 mmol) and MeOH (200 mL). Then Pd/C (10% wt, 900 mg) was added. The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10 to 1:8). This resulted in 7.2 g (77%) of the title compound as brown oil. MS-ESI: 196.1 (M+1).

3-Fluoro-2,6-diisopropylbenzenamine Step 1: 2,6-Dibromo-4-chloro-3-fluorobenzenamine

Into a 500-mL round-bottom flask, was placed 4-chloro-3-fluorobenzenamine (5.08 g, 34.9 mmol), ACN (200 mL), and NB S (18.69 g, 105.0 mmol). The resulting solution was stirred for 12 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:200 to 1:100). This resulted in 9.7 g (92%) of the title compound as a light yellow solid. MS-ESI: 303.8, 305.8, 301.8 (M+1).

Step 2: 4-Chloro-3-fluoro-2,6-di(prop-1-en-2-yl)benzenamine

Into a 500-mL round-bottom flask purged with and maintained under nitrogen, was placed 2,6-dibromo-4-chloro-3-fluorobenzenamine (9.03 g, 29.8 mmol), dioxane (200 mL), water (20 mL), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (15.12 g, 89.98 mmol), Cs₂CO₃ (29.34 g, 90.05 mmol), and Pd(dppf)Cl₂ (2.20 g, 3.01 mmol). The resulting solution was stirred for 12 h at 100° C. and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 4.3 g (64%) of the title compound as yellow oil. MS-ESI: 226.1, 228.1 (M+1).

Step 3: 3-Fluoro-2,6-diisopropylbenzenamine

Into a 250-mL pressure tank reactor (10 atm) purged with and maintained under nitrogen, was placed 4-chloro-3-fluoro-2,6-di(prop-1-en-2-yl)benzenamine (4.3 g, 19.1 mmol), MeOH (100 mL), and TEA (2.0 g, 19.8 mmol). Then Pd/C (10% wt, 0.5 g) was added. The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 7 days at 100° C. under an atmosphere of hydrogen. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5 to 1:3). This resulted in 3.6 g (97%) of the title compound as a light yellow oil. MS-ESI: 196.1 (M+1).

4-Chloro-2,6-diisopropylbenzenamine Step 1: 4-Chloro-2,6-diisopropylbenzenamine

Into a 100-mL round-bottom flask, was placed 2,6-diisopropylbenzenamine (5 g, 28.2 mmol), DMF (20 mL), and NCS (4.9 g, 36.7 mmol). The resulting solution was stirred for 15 h at RT and then was diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of DCM and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10 to 1:5). This resulted in 3.7 g (62%) of the title compound as brown oil. MS-ESI: 212.1, 214.1 (M+1).

4-Amino-3,5-diisopropylbenzonitrile Step 1: 4-Amino-3,5-diisopropylbenzonitrile

Into a 100-mL round-bottom flask purged with and maintained under nitrogen, was placed 4-bromo-2,6-diisopropylbenzenamine (commercial available, 5.1 g, 19.9 mmol), DMF (30 mL), CuCN (2.16 g, 23.9 mmol), CuI (380 mg, 2.00 mmol), KI (664 mg, 3.98 mmol), and DMEDA (2.0 mL). The resulting solution was stirred for 24 h at 100° C. and then was diluted with 30 mL of water. The solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:30 to 1:20). This resulted in 1.2 g (30%) of the title compound as a yellow solid. MS-ESI: 203.1 (M+1).

4-Amino-3,5-diisopropylbenzamide Step 1: 4-Amino-3,5-diisopropylbenzamide

Into a 25-mL round-bottom flask, was placed 4-amino-3,5-diisopropylbenzonitrile (141 mg, 0.70 mmol), DMSO (3 mL), K₂CO₃ (70 mg, 0.51 mmol), and H₂O₂ (0.2 mL). The resulting solution was stirred for 3 h at RT and then was diluted with 5 mL of water. The resulting solution was extracted with 3×5 mL of ethyl acetate and the organic layers combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. This resulted in 145 mg (94%) of the title compound as a yellow solid. MS-ESI: 221.2 (M+1).

Methyl 4-amino-3,5-diisopropylbenzoate Step 1: Methyl 4-amino-3,5-diisopropylbenzoate

Into a 100-mL round-bottom flask, was placed 4-bromo-2,6-diisopropylbenzenamine (2.161 g, 8.44 mmol), DMF (20 mL), MeOH (20 mL), and Pd(dppf)Cl₂ (1.24 g, 1.69 mmol). The resulting solution was stirred for 16 h at 120° C. under an atmosphere of CO and then diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:60 to 1:40). This resulted in 341 mg (17%) of the title compound as yellow oil. MS-ESI: 236.2 (M+1).

8-Chloro-1,2,3,5,6,7-hexahydros-indacen-4-amine Step 1: 8-Chloro-1,2,3,5,6,7-hexahydros-indacen-4-amine

Into a 100-mL round-bottom flask, was placed 1,2,3,5,6,7-hexahydros-indacen-4-amine (1.73 g, 9.99 mmol), DMF (10 mL), and NCS (1.47 g, 11.0 mmol). The resulting solution was stirred for 12 h at RT and then was diluted with 50 mL of DCM. The resulting mixture was washed with 3×10 mL of water. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10 to 1:5). This resulted in 1.88 g (91%) of the title compound as a yellow solid. MS-ESI: 208.1, 210.1 (M+1).

8-Fluoro-1,2,3,5,6,7-hexahydros-indacen-4-amine Step 1: 8-Nitro-1,2,3,5,6,7-hexahydros-indacen-4-amine

Into a 500-mL round-bottom flask, was placed 1,2,3,5,6,7-hexahydros-indacen-4-amine (8 g, 46.17 mmol), EtOH (200 mL), and 2,3,5,6-tetrabromo-4-methyl-4-nitrocyclohexa-2,5-dienone (21.6 g, 46.08 mmol). The resulting solution was stirred for 12 h at RT and then was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:50 to 1:30). This resulted in 5 g (50%) of the title compound as a yellow solid. MS-ESI: 219.1 (M+1).

Step 2: 4-Fluoro-8-nitro-1,2,3,5,6,7-hexahydros-indacene

Into a 100-mL round-bottom flask, was placed 8-nitro-1,2,3,5,6,7-hexahydros-indacen-4-amine (5 g, 22.91 mmol), HF/Py (70% wt, 20 mL). This was followed by the addition of 3-methylbutyl nitrite (3 g, 25.61 mmol) dropwise with stirring at 0° C. The resulting solution was stirred for 2 h at RT and then was diluted with 50 mL of water. The resulting solution was extracted with 3×50 mL of DCM and the organic layers combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. This resulted in 4 g (crude, 79%) of the title compound as brown oil.

Step 3: 8-Fluoro-1,2,3,5,6,7-hexahydros-indacen-4-amine

Into a 100-mL round-bottom flask, was placed 4-fluoro-8-nitro-1,2,3,5,6,7-hexahydros-indacene (4 g, 18.08 mmol) and MeOH (50 mL). Then Pd/C (10% wt, 0.5 g) was added. The flask was evacuated and flushed three times with hydrogen. The resulting solution was stirred for 12 h at RT under an atmosphere of hydrogen. The solids were filtered out and the mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:10 to 1:5). This resulted in 2 g (58%) of the title compound as a white solid. MS-ESI: 192.1 (M+1).

8-Amino-1,2,3,5,6,7-hexahydros-indacene-4-carbonitrile Step 1: 8-Amino-1,2,3,5,6,7-hexahydros-indacene-4-carbonitrile

Into a 50-mL round-bottom flask purged with and maintained under nitrogen, was placed 8-bromo-1,2,3,5,6,7-hexahydros-indacen-4-amine (725 mg, 2.88 mmol), DMF (10 mL), t-BuOK (330 mg, 2.90 mmol), CuCN (386 mg, 4.32 mmol), Pd(dppf)Cl₂ (424 mg, 0.58 mmol), and Pd(PPh₃)₄ (334 mg, 0.29 mmol). The resulting solution was stirred for 12 h at 120° C. and diluted with 20 mL of water. The resulting solution was extracted with 3×20 mL ethyl acetate and the organic layers combined and dried over anhydrous Na₂SO₄, then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:60 to 1:40). This resulted in 192 mg (34%) of the title compound as a yellow solid. MS-ESI: 199.1 (M+1).

Example 2

3-Chloro-N-(8-chloro-1,2,3,5,6,7-hexahydros-indacen-4-ylcarbamoyl)-5-(2-hydroxypropan-2-yl) benzenesulfonamide (Scheme 2)

Into a 50-mL round-bottom flask purged with and maintained under nitrogen, was placed 8-chloro-1,2,3,5,6,7-hexahydros-indacen-4-amine (72 mg, 0.35 mmol), THF (3 mL), TEA (35 mg, 0.35 mmol), BTC (35 mg, 0.12 mmol). The resulting solution was stirred for 2 h at 65° C. and then was concentrated under vacuum. The above mixture diluted in THF (1 mL) was added to a solution of 3-chloro-5-(2-hydroxypropan-2-yl)benzenesulfonamide (86 mg, 0.34 mmol) and CH₃ONa (94 mg, 1.74 mmol) in THF (3 mL). The resulting solution was stirred for 3 h at RT and then was concentrated under vacuum. The crude product was purified by Prep-HPLC using method E eluted with a gradient of 30˜60% ACN. This resulted in 42.0 mg (25%) of the title compound as a white solid. MS-ESI: 483.1 (M+1). ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.03 (s, 1H), 7.85 (s, 1H), 7.73 (s, 1H), 2.86 (t, J=7.6 Hz, 4H), 2.72 (t, J=7.2 Hz, 4H), 2.07-1.99 (m, 4H), 1.53 (s, 6H).

Example 3

N-(4-cyano-2,6-diisopropylphenylcarbamoyl)-3-fluoro-5-(2-hydroxypropan-2-yl)benzenesulfonamide (Scheme 3)

Into a 50-mL round-bottom flask purged with and maintained under nitrogen, was placed 4-amino-3,5-diisopropylbenzonitrile (59 mg, 0.29 mmol), THF (3 mL), TEA (30 mg, 0.30 mmol), and BTC (25 mg, 0.08 mmol). The resulting solution was stirred for 2 h at 65° C. and then was concentrated under vacuum.

The above mixture diluted in THF (1 mL) was added to a solution of 3-fluoro-5-(2-hydroxypropan-2-yl)benzenesulfonamide (67 mg, 0.29 mmol) and DBU (66 mg, 0.43 mmol) in THF (3 mL). The resulting solution was stirred for 2 h at RT and then was concentrated under vacuum. The crude product was purified by Prep-HPLC using method E eluted with a gradient of 10˜30% ACN. This resulted in 42.3 mg (32%) of title compound as a white solid. MS-ESI: 460.3 (M+1). ¹H NMR (400 MHz, CD₃OD-d₄) δ 7.97 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.54-7.49 (m, 1H), 7.49 (s, 2H), 3.02-2.95 (m, 2H), 1.55 (s, 6H), 1.11 (d, J=4.8 Hz, 12H).

Example 4

N-(1,2,3,5,6,7-hexahydros-indacen-4-ylcarbamoyl)-3,5-bis(2-hydroxypropan-2-yl)benzenesulfonamide (Scheme 4)

Into a 50-mL round-bottom flask purged with and maintained under nitrogen, was placed 1,2,3,5,6,7-hexahydros-indacen-4-amine (64 mg, 0.37 mmol), THF (2 mL), TEA (38 mg, 0.38 mmol), and BTC (37 mg, 0.12 mmol). The resulting solution was stirred for 2 h at 65° C. and then was concentrated under vacuum. The above mixture diluted in DCM (1 mL) was added to a solution of 3,5-bis(2-hydroxypropan-2-yl)benzenesulfonamide (100 mg, 0.37 mmol) and TEA (38 mg, 0.38 mmol) in DCM (3 mL). The resulting solution was stirred for 3 h at RT and then was concentrated under vacuum. The crude product was purified by Prep-HPLC using method E eluted with a gradient of 10˜60% ACN. This resulted in 90 mg (52%) of the title compound as a white solid. MS-ESI: 471.2 (M−1). ¹H NMR (400 MHz, CD₃OD-d₄) δ 8.01 (s, 2H), 7.91 (s, 1H), 6.91 (s, 1H), 2.81 (t, J=7.2 Hz, 4H), 2.57 (t, J=6.8 Hz, 4H), 2.00-1.92 (m, 4H), 1.55 (s, 12H).

Example 5

N-(1,2,3,5,6,7-hexahydros-indacen-4-ylcarbamoyl)-3-(2-hydroxypropan-2-yl)-5-morpholinobenzenesulfonamide (Scheme 5)

Into a 50-mL round-bottom flask purged with and maintained under nitrogen, was placed 1,2,3,5,6,7-hexahydros-indacen-4-amine (71 mg, 0.41 mmol), THF (20 mL), TEA (42 mg, 0.42 mmol), and BTC (37 mg, 0.12 mmol). The resulting solution was stirred for 2 h at 65° C. and then was concentrated under vacuum. The above mixture diluted in THF (3 mL) was added to a solution of 3-(2-hydroxypropan-2-yl)-5-morpholinobenzenesulfonamide (110 mg, 0.37 mmol) and TEA (42 mg, 0.42 mmol) in THF (5 mL). The resulting solution was stirred for 3 h at RT and then was concentrated under vacuum. The crude product was purified by Prep-HPLC using method E eluted with a gradient of 10˜60% ACN. This resulted in 88.6 mg (43%) of the title compound as a white solid. MS-ESI: 500.2 (M+1). ¹H NMR (400 MHz, CD₃OD-d₄) δ 7.57 (s, 1H), 7.43 (s, 1H), 7.36 (s, 1H), 6.92 (s, 1H), 3.83 (t, J=4.8 Hz, 4H), 3.21 (t, J=4.8 Hz, 4H), 2.82 (t, J=7.2 Hz, 4H), 2.69 (t, J=7.2 Hz, 4H), 2.07-1.94 (m, 4H), 1.53 (s, 6H).

TABLE 8 Examples in the following table were prepared using similar conditions as described in Example 2 and Scheme 2 from appropriate starting materials. Mass Example Spec # Compound Structure IUPAC Name [M − H]⁻ 6 120

3-chloro-N-(2,6- diisopropylphenyl carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 435.1 (M − OH)⁺ 7 101

3-chloro-N- (1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-5- (2- hydroxypropan-2- yl)benzenesulfona- mide 447.2 8 124

4-(3-(3-chloro-5- (2- hydroxypropan-2- yl)phenylsulfonyl) ureido)-3,5- diisopropylbenza- mide 496.2 (M + 1) 9 114

3-fluoro-N-(8- fluoro-1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-5- (2- hydroxypropan-2- yl)benzenesulfona- mide 449.1 10 125

N-(2,6- diisopropylphenyl carbamoyl)-3- fluoro-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 437.2 (M + 1) 11 102

3-fluoro-N- (1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-5- (2- hydroxypropan-2- yl)benzenesulfona- mide 431.1 12 147

N-(4-cyano-2,6- diisopropylphenyl carbamoyl)-3-(2- hydroxypropan-2- yl)benzenesulfona- mide 442.1

TABLE 9 Examples in the following table were prepared using similar conditions as described in Example 3 and Scheme 3 from appropriate starting materials. Mass Example Spec # Compound Structure IUPAC Name [M − H]⁻ 13 144

3-fluoro-N-(3- fluoro-2,6- diisopropylphenyl- carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 453.1 14 150

N-(4-chloro-2,6- diisopropylphenyl- carbamoyl)-3- fluoro-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 469.2 15 109

N-(8-cyano- 1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-3- fluoro-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 456.1 16 127

3-fluoro-N-(4- fluoro-2,6- diisopropylphenyl- carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 453.2 17 131

2-fluoro-N- (1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 415.1 (M − OH)⁺ 18 137

3-chloro-N-(3- fluoro-2,6- diisopropylphenyl- carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 469.2 19 138

3-chloro-N-(4- cyano-2,6- diisopropylphenyl- carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 476.2 20 123

3-chloro-N-(4- fluoro-2,6- diisopropylphenyl- carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 469.2 21 113

3-chloro-N-(8- fluoro-1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 467.1 (M + 1) 22 108

3-chloro-N-(8- cyano-1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 472.1 23 154

3-chloro-N-(4- chloro-2,6- diisopropylphenyl- carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 485.1 24 112

3-cyano-N-(8- fluoro-1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 456.1 25 106

3-cyano-N- (1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 438.1 26 110

N-(8-chloro- 1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-3- cyano-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 474.2 (M + 1) 27 117

3-cyano-N-(4- fluoro-2,6- diisopropylphenyl- carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 460.3 28 116

3-cyano-N-(4- cyano-2,6- diisopropylphenyl- carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 467.2 29 145

N-(4-chloro-2,6- diisopropylphenyl- carbamoyl)-3- cyano-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 476.1 30 148

3-cyano-N-(3- fluoro-2,6- diisopropylphenyl- carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 460.1 31 115

3-cyano-N-(2,6- diisopropylphenyl- carbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 442.1 32 107

3-cyano-N-(8- cyano-1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-5-(2- hydroxypropan-2- yl)benzenesulfona- mide 463.1 33 141

N-(3-fluoro-2,6- diisopropylphenyl- carbamoyl)-3-(2- hydroxypropan-2- yl)benzenesulfona- mide 435.2 34 111

N-(8-fluoro- 1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-3-(2- hydroxypropan-2- yl)benzenesulfona- mide 431.2 35 105

N-(8-cyano- 1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-3-(2- hydroxypropan-2- yl)benzenesulfona- mide 438.2 36 158

methyl 4-(3-(3-(2- hydroxypropan-2- yl)phenylsulfonyl) ureido)-3,5- diisopropylbenzoate 475.2 37 167

N-(1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-4-(2- hydroxypropan-2- yl)benzenesulfona- mide 415.2 (M + 1) 38 166

N-(1,2,3,5,6,7- hexahydros- indacen-4- ylcarbamoyl)-6-(2- hydroxypropan-2- yl)pyridine-3- sulfonamide 414.1 39 171

methyl 3-(N-(4- chloro-2,6- diisopropylphenyl- carbamoyl) sulfamoyl)-4- fluorobenzoate 471.1 (M + 1)

TABLE 10 Examples in the following table were prepared using similar conditions as described in Example 4 and Scheme 4 from appropriate starting materials. Mass Example Spec # Compound Structure IUPAC Name [M − H]⁻ 40 155

N-(3-fluoro-2,6- diisopropylphenyl- carbamoyl)-3,5- bis(2- hydroxypropan-2- yl)benzene- sulfonamide 493.3 41 149

N-(1,2,3,5,6,7- hexahydro- sindacen-4- ylcarbamoyl)-3- (2-hydroxy- propan-2-yl)-5- (pyridin-4-yl) benzene- sulfonamide 492.2 (M + 1) 42 159

N-(3-fluoro-2,6- diisopropyl- phenylcarbamoyl)- 3-(2-hydroxy- propan-2-yl)-5- (pyridin-4-yl) benzene- sulfonamide 514.2 (M + 1) 43 151

N-(1,2,3,5,6,7- hexahydro- sindacen-4- ylcarbamoyl)-5- (2-hydroxy- propan-2-yl) biphenyl-3- sulfonamide 473.2 (M − OH)⁺ 44 153

N-(3-fluoro-2,6- diisopropylphenyl- carbamoyl)-5-(2- hydroxypropan-2- yl)biphenyl-3- sulfonamide 495.3 (M − OH)⁺ 45 160

N-(8-fluoro- 1,2,3,5,6,7- hexahydro- sindacen-4- ylcarbamoyl)-4- (2-hydroxy- propan-2-yl) benzene- sulfonamide 433.1 46 161

N-(8-chloro- 1,2,3,5,6,7- hexahydro- sindacen-4- ylcarbamoyl)-4- (2-hydroxy- propan-2-yl) benzene- sulfonamide 449.1 47 164

N-(8-cyano- 1,2,3,5,6,7- hexahydro- sindacen-4- ylcarbamoyl)-4- (2-hydroxy- propan-2-yl) benzene- sulfonamide 440.1 48 162

N-(4-chloro- 2,6-diisopropyl- phenyl- carbamoyl)-4- (2-hydroxy- propan-2-yl) benzene- sulfonamide 453.2 49 165

N-(4-fluoro- 2,6-diisopropyl- phenyl- carbamoyl)-4- (2-hydroxy- propan-2-yl) benzene- sulfonamide 437.2 50 168

N-(4-cyano- 2,6-diisopropyl- phenyl- carbamoyl)-4- (2-hydroxy- propan-2-yl) benzene- sulfonamide 444.1 51 169

N-(2,6- diisopropyl- phenyl- carbamoyl)-4- (2-hydroxy- propan-2-yl) benzene- sulfonamide 419.1 52 170

N-(3-fluoro- 2,6-diisopropyl- phenyl- carbamoyl)-4- (2-hydroxy- propan-2-yl) benzene- sulfonamide 437.3

TABLE 11 The example in the following table was prepared using similar conditions as described in Example 5 and Scheme 5 from appropriate starting materials. Mass Example Spec # Compound Structure IUPAC Name [M + H]⁺ 53 157

N-(3-fluoro- 2,6-diisopropyl- phenyl- carbamoyl)-3- (2-hydroxy- propan-2-yl)- 5-morpholino- benzene- sulfonamide 522.3 54 163

N-(1,2,3,5,6,7- hexahydro- sindacen-4- ylcarbamoyl)- 3-(hydroxy- methyl)-4-(2- hydroxy- propan-2-yl) benzene- sulfonamide 443.2

Bioassay:

IL-1β Production in PMA-Differentiated THP-1 Cells Stimulated With Gramicidin.

Procedure 1:

Cell culture-THP-1 cells were purchased from the American Type Culture Collection and sub-cultured according to instructions from the supplier. Prior to experiments, cells were cultured in RPMI 1640 containing 10% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml), and maintained in log phase prior to experimental setup. Prior to the experiment THP-1 were treated with PMA (Phorbol 12-myristate 13-acetate) (10 μg/ml) for 24 hours. The day of the experiment the media was removed and attaching cells were treated with trypsin for 2 minutes, cells were then collected, washed with PBS (phosphate buffer saline), spin down, resuspended in 2% heat inactivated FBS with RPMI at a concentration of 1×106 cells/ml, and 100 μl was plated in a 96 well plate. Cells were incubated with compounds for 1 hours and then stimulated with Gramicidin (5 μM) (Enzo) for 2 hours. Cell free supernatant was collected and the production of IL-1β was evaluated by ELISA. Compounds were dissolved in dimethyl sulfoxide (DMSO) and added to the culture medium to achieve desired concentration (e.g. 100, 30, 10, 3, 1, 0.3 or 0.1 μM). A vehicle only control was run concurrently with each experiment. Final DMSO concentration was 1%. Compounds exhibit a dose-related inhibition of IL-1β production in PMA-differentiated THP-1 cells.

Procedure 2:

THP-1 cells were purchased from the American Type Culture Collection and sub-cultured according to instructions from the supplier. Prior to experiments, cells were cultured in complete RPMI 1640 (containing 10% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml)), and maintained in log phase prior to experimental setup. Prior to the experiment THP-1 were treated with PMA (Phorbol 12-myristate 13-acetate) (20 ng/ml) for 16-18 hours. On the day of the experiment the media was removed and adherent cells were detached with trypsin for 5 minutes. Cells were then harvested, washed with complete RPMI 1640, spun down, resuspended in RPMI 1640 (containing 2% heat inactivated FBS, penicillin (100 units/ml) and streptomycin (100 μg/ml). The cells were plated in a 384-well plate at a density of 50,000 cells/well (final assay volume 50 μl). Compounds were dissolved in dimethyl sulfoxide (DMSO) and added to the culture medium to achieve desired concentration (e.g. 100, 33, 11, 3.7, 1.2, 0.41, 0.14, 0.046, 0.015, 0.0051, 0.0017 μM). Cells were incubated with compounds for 1 hour and then stimulated with gramicidin (5 μM) (Enzo) for 2 hours. Cell free supernatant was collected and the production of IL-1β was evaluated by HTRF (cisbio). A vehicle only control was run concurrently with each experiment. Final DMSO concentration was 0.38%. Compounds exhibited a concentration-dependent inhibition of IL-1β production in PMA-differentiated THP-1 cells.

IC₅₀ values (μm) of compounds of the formulae herein tested in accordance with the protocol above gave IC₅₀ values of less than about 30 μm.

A number of embodiments of the invention have been described. Nevertheless, it will be understood that various modifications may be made without departing from the spirit and scope of the invention. Accordingly, other embodiments are within the scope of the following claims. 

We claim:
 1. A compound selected from the group consisting of compounds in the Table below: Com- pound Structure 101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

131

135

136

137

138

142

143

144

145

146

147

148

149

151

153

154

155

157

158

159

160

161

163

164

166

167

168

169

170

and 171

or pharmaceutically acceptable salts thereof.
 2. A pharmaceutical composition comprising a compound or salt as claimed in claim 1 and one or more pharmaceutically acceptable excipients. 